ORLANDO – Adding rituximab to standard intensive chemotherapy significantly improved event-free survival in adults with Philadelphia-negative, CD20-positive B-cell precursor acute lymphoblastic leukemia in the phase III GRAALL-R 2005 study.

Rituximab (Rituxan) is already being used to improve outcomes in patients with lymphoma, and non-randomized data support addition of the anti-CD20 monoclonal antibody to chemotherapy in B-cell precursor (BCP) ALL, where the CD20 antigen is expressed in 30% to 40% of patients at diagnosis.

In the randomized GRAALL-R 2005, 2-year event-free survival (EFS) was 65% in the rituximab arm vs. 52% in the control arm (hazard ratio, 0.66; P = .038).

Patrice Wendling/Frontline Medical News

This difference is not explained by the early response rates, which were very close in both arms after one or two induction courses (92% vs. 90%; P = .63), Dr. Sébastien Maury, Hôpital Henri Mondor in Créteil, France, said during the plenary session at the annual meeting of the American Society of Hematology (Ab. 1).

The beneficial effect of rituximab, however, was clearly related to the cumulative incidence of relapse at 18% with vs. 32% without rituximab (HR, 0.52; P = .017).

Despite this advantage, overall survival was similar between patients given chemotherapy with and without rituximab (71% vs. 64%; HR, 0.70; P = .095), he said.

After censoring for patients not receiving allogeneic stem cell transplant in first complete remission, however, rituximab significantly prolonged 2-year EFS (HR, 0.59; P = .021) as well as overall survival (HR, 0.55; P = .018), Dr. Maury said.

“We thus recommend that the addition of rituximab become a new standard of care for these patients, although some aspects including the definition of the optimal dose needs to be determined in further studies,” he concluded.

Dr. Adele Fielding of University College London, who introduced the study at the meeting, said, “For me, the prior knowledge that the drug can be safely already added to chemotherapy in other settings provides profound comfort in a disease in which so many people are already damaged by the current therapies we offer.”

Also, of importance is the potential relevance of rituximab in patients in whom CD20 is present on fewer than 20% of blasts at diagnosis.

Key questions that remain in rituximab therapy of ALL beyond overall benefit include early and late toxicities and how best to judge response and when, she said. Synergies with other agents and the mechanism of action will also require clarification, especially which effector cells are relevant to ensure that agents are not used with rituximab that destroy the optimal chance for response.

“Finally, the cost of introducing novel agents cannot be ignored, even in well-developed economies, and I am hopeful that the cost of this drug will be variable for many countries and many patients.” Dr. Fielding said.

Study details

A total of 220 patients, aged 18-59 years, with newly diagnosed CD20-positive Ph-negative BCP-ALL were randomized to the pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) chemotherapy protocol with or without rituximab 375 mg/m² given during induction (day 1 and 7), salvage reinduction when needed (day 1 and 7), consolidation blocks (6 infusions), late intensification (day 1 and 7, and the first year of maintenance [6 infusions], for a total of 16-18 infusions. Allogeneic stem cell transplant (SCT) was offered after consolidation blocks 1 or 2 to patients with one or more high-risk criteria and an available donor. CD20-positivity was defined as expression of CD20 in more than 20% of leukemia blasts.

Eleven patients were excluded from the analysis because of non–ineligibility criteria, leaving 209 patients in the modified intent-to-treat analysis. Their median age was 40.2 years and 67% had high-risk ALL.

Rates of postinduction minimal residual disease less than 10^–4 were 65% and 61% in the rituximab and control arms among 85 evaluable patients(P = .82), and rates of postconsolidation minimal residual disease less than 10^–4 were 91% and 82% among 80 evaluable patients (P = .31), Dr. Maury reported.

Notably, more patients in the rituximab arm received allogeneic SCT in their first complete remission (34% vs. 20%; P = .029).

The cumulative incidence of death in first complete remission was 12% in both arms.

In multivariate analysis, rituximab impacted EFS, together with age, central nervous system involvement, white blood cells, or CD20 expression at diagnosis. A preferential effect with rituximab was seen in patients with high CD20 levels that deserves further evaluation, he observed.

There was no difference in the incidence of adverse events between the rituximab and control arms, although there was a trend for more infectious events with rituximab (71 events vs. 55 events), Dr. Maury said.

Allergic events – all but one from aspergillosis – were significantly more common in the control arm (2 events vs. 14 events; P = .002).

The Group for Research in Adult Acute Lymphoblastic Leukemia sponsored the study. Dr. Maury reported having no disclosures.

[email protected]

ORLANDO – Adding rituximab to standard intensive chemotherapy significantly improved event-free survival in adults with Philadelphia-negative, CD20-positive B-cell precursor acute lymphoblastic leukemia in the phase III GRAALL-R 2005 study.

Rituximab (Rituxan) is already being used to improve outcomes in patients with lymphoma, and non-randomized data support addition of the anti-CD20 monoclonal antibody to chemotherapy in B-cell precursor (BCP) ALL, where the CD20 antigen is expressed in 30% to 40% of patients at diagnosis.

In the randomized GRAALL-R 2005, 2-year event-free survival (EFS) was 65% in the rituximab arm vs. 52% in the control arm (hazard ratio, 0.66; P = .038).

Patrice Wendling/Frontline Medical News

This difference is not explained by the early response rates, which were very close in both arms after one or two induction courses (92% vs. 90%; P = .63), Dr. Sébastien Maury, Hôpital Henri Mondor in Créteil, France, said during the plenary session at the annual meeting of the American Society of Hematology (Ab. 1).

The beneficial effect of rituximab, however, was clearly related to the cumulative incidence of relapse at 18% with vs. 32% without rituximab (HR, 0.52; P = .017).

Despite this advantage, overall survival was similar between patients given chemotherapy with and without rituximab (71% vs. 64%; HR, 0.70; P = .095), he said.

After censoring for patients not receiving allogeneic stem cell transplant in first complete remission, however, rituximab significantly prolonged 2-year EFS (HR, 0.59; P = .021) as well as overall survival (HR, 0.55; P = .018), Dr. Maury said.

“We thus recommend that the addition of rituximab become a new standard of care for these patients, although some aspects including the definition of the optimal dose needs to be determined in further studies,” he concluded.

Dr. Adele Fielding of University College London, who introduced the study at the meeting, said, “For me, the prior knowledge that the drug can be safely already added to chemotherapy in other settings provides profound comfort in a disease in which so many people are already damaged by the current therapies we offer.”

Also, of importance is the potential relevance of rituximab in patients in whom CD20 is present on fewer than 20% of blasts at diagnosis.

Key questions that remain in rituximab therapy of ALL beyond overall benefit include early and late toxicities and how best to judge response and when, she said. Synergies with other agents and the mechanism of action will also require clarification, especially which effector cells are relevant to ensure that agents are not used with rituximab that destroy the optimal chance for response.

“Finally, the cost of introducing novel agents cannot be ignored, even in well-developed economies, and I am hopeful that the cost of this drug will be variable for many countries and many patients.” Dr. Fielding said.

Study details

A total of 220 patients, aged 18-59 years, with newly diagnosed CD20-positive Ph-negative BCP-ALL were randomized to the pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) chemotherapy protocol with or without rituximab 375 mg/m² given during induction (day 1 and 7), salvage reinduction when needed (day 1 and 7), consolidation blocks (6 infusions), late intensification (day 1 and 7, and the first year of maintenance [6 infusions], for a total of 16-18 infusions. Allogeneic stem cell transplant (SCT) was offered after consolidation blocks 1 or 2 to patients with one or more high-risk criteria and an available donor. CD20-positivity was defined as expression of CD20 in more than 20% of leukemia blasts.

Eleven patients were excluded from the analysis because of non–ineligibility criteria, leaving 209 patients in the modified intent-to-treat analysis. Their median age was 40.2 years and 67% had high-risk ALL.

Rates of postinduction minimal residual disease less than 10^–4 were 65% and 61% in the rituximab and control arms among 85 evaluable patients(P = .82), and rates of postconsolidation minimal residual disease less than 10^–4 were 91% and 82% among 80 evaluable patients (P = .31), Dr. Maury reported.

Notably, more patients in the rituximab arm received allogeneic SCT in their first complete remission (34% vs. 20%; P = .029).

The cumulative incidence of death in first complete remission was 12% in both arms.

In multivariate analysis, rituximab impacted EFS, together with age, central nervous system involvement, white blood cells, or CD20 expression at diagnosis. A preferential effect with rituximab was seen in patients with high CD20 levels that deserves further evaluation, he observed.

There was no difference in the incidence of adverse events between the rituximab and control arms, although there was a trend for more infectious events with rituximab (71 events vs. 55 events), Dr. Maury said.

Allergic events – all but one from aspergillosis – were significantly more common in the control arm (2 events vs. 14 events; P = .002).

The Group for Research in Adult Acute Lymphoblastic Leukemia sponsored the study. Dr. Maury reported having no disclosures.

[email protected]

ORLANDO – Adding rituximab to standard intensive chemotherapy significantly improved event-free survival in adults with Philadelphia-negative, CD20-positive B-cell precursor acute lymphoblastic leukemia in the phase III GRAALL-R 2005 study.

Rituximab (Rituxan) is already being used to improve outcomes in patients with lymphoma, and non-randomized data support addition of the anti-CD20 monoclonal antibody to chemotherapy in B-cell precursor (BCP) ALL, where the CD20 antigen is expressed in 30% to 40% of patients at diagnosis.

In the randomized GRAALL-R 2005, 2-year event-free survival (EFS) was 65% in the rituximab arm vs. 52% in the control arm (hazard ratio, 0.66; P = .038).

Patrice Wendling/Frontline Medical News

This difference is not explained by the early response rates, which were very close in both arms after one or two induction courses (92% vs. 90%; P = .63), Dr. Sébastien Maury, Hôpital Henri Mondor in Créteil, France, said during the plenary session at the annual meeting of the American Society of Hematology (Ab. 1).

The beneficial effect of rituximab, however, was clearly related to the cumulative incidence of relapse at 18% with vs. 32% without rituximab (HR, 0.52; P = .017).

Despite this advantage, overall survival was similar between patients given chemotherapy with and without rituximab (71% vs. 64%; HR, 0.70; P = .095), he said.

After censoring for patients not receiving allogeneic stem cell transplant in first complete remission, however, rituximab significantly prolonged 2-year EFS (HR, 0.59; P = .021) as well as overall survival (HR, 0.55; P = .018), Dr. Maury said.

“We thus recommend that the addition of rituximab become a new standard of care for these patients, although some aspects including the definition of the optimal dose needs to be determined in further studies,” he concluded.

Dr. Adele Fielding of University College London, who introduced the study at the meeting, said, “For me, the prior knowledge that the drug can be safely already added to chemotherapy in other settings provides profound comfort in a disease in which so many people are already damaged by the current therapies we offer.”

Also, of importance is the potential relevance of rituximab in patients in whom CD20 is present on fewer than 20% of blasts at diagnosis.

Key questions that remain in rituximab therapy of ALL beyond overall benefit include early and late toxicities and how best to judge response and when, she said. Synergies with other agents and the mechanism of action will also require clarification, especially which effector cells are relevant to ensure that agents are not used with rituximab that destroy the optimal chance for response.

“Finally, the cost of introducing novel agents cannot be ignored, even in well-developed economies, and I am hopeful that the cost of this drug will be variable for many countries and many patients.” Dr. Fielding said.

Study details

A total of 220 patients, aged 18-59 years, with newly diagnosed CD20-positive Ph-negative BCP-ALL were randomized to the pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) chemotherapy protocol with or without rituximab 375 mg/m² given during induction (day 1 and 7), salvage reinduction when needed (day 1 and 7), consolidation blocks (6 infusions), late intensification (day 1 and 7, and the first year of maintenance [6 infusions], for a total of 16-18 infusions. Allogeneic stem cell transplant (SCT) was offered after consolidation blocks 1 or 2 to patients with one or more high-risk criteria and an available donor. CD20-positivity was defined as expression of CD20 in more than 20% of leukemia blasts.

Eleven patients were excluded from the analysis because of non–ineligibility criteria, leaving 209 patients in the modified intent-to-treat analysis. Their median age was 40.2 years and 67% had high-risk ALL.

Rates of postinduction minimal residual disease less than 10^–4 were 65% and 61% in the rituximab and control arms among 85 evaluable patients(P = .82), and rates of postconsolidation minimal residual disease less than 10^–4 were 91% and 82% among 80 evaluable patients (P = .31), Dr. Maury reported.

Notably, more patients in the rituximab arm received allogeneic SCT in their first complete remission (34% vs. 20%; P = .029).

The cumulative incidence of death in first complete remission was 12% in both arms.

In multivariate analysis, rituximab impacted EFS, together with age, central nervous system involvement, white blood cells, or CD20 expression at diagnosis. A preferential effect with rituximab was seen in patients with high CD20 levels that deserves further evaluation, he observed.

There was no difference in the incidence of adverse events between the rituximab and control arms, although there was a trend for more infectious events with rituximab (71 events vs. 55 events), Dr. Maury said.

Allergic events – all but one from aspergillosis – were significantly more common in the control arm (2 events vs. 14 events; P = .002).

The Group for Research in Adult Acute Lymphoblastic Leukemia sponsored the study. Dr. Maury reported having no disclosures.

[email protected]

Orthopedic surgery is going through a time of remarkable change. Health care reform, heightened public scrutiny, shifting population demographics, increased reliance on the Internet for information, ongoing metamorphosis of our profession into a business, and lack of consistent high-quality clinical evidence have created a new frontier of challenges and opportunities. At heart are the needs to deliver high-quality education that is in line with new technological media, to reclaim our ability to guide musculoskeletal care at the policymaking level, to fortify our long-held tradition of ethical responsibility, to invest in research and the training of physician-scientists, to maintain unity among the different subspecialties, and to increase female and minority representation. Never before has understanding and applying the key tenets of our philosophy as orthopedic surgeons been more crucial.

The changing landscape of orthopedic practice has been an unsettling topic in many of the American Academy of Orthopaedic Surgeons (AAOS) presidential addresses in recent years.^1-11 What are the challenges and what can we learn moving forward? In this article, we seek to answer these questions by drawing insights from the combined experience and wisdom of past AAOS presidents since the turn of the 21st century.

Education

Education is the cornerstone of providing quality musculoskeletal care¹² and staying up to date with technological advances.¹³ The modes of education delivery, however, have changed. No longer is orthopedic education confined to tangible textbooks and journal articles, nor is it limited to those of us in the profession. Instead, orthopedic education has shifted toward online learning¹⁴ and is available to patients and nonorthopedic providers.¹² With more patients gaining access to rapidly growing online resources, a unique challenge has arisen: an abundance of data with variable quality of evidence influencing the decision-making process. This has created what Richard Kyle¹⁵ described as the “trap of the new technology war,” where patient misinformation and direct-to-consumer marketing can lead to dangerous musculoskeletal care delivery, including unrealistic patient expectations.³ To compound the problem, our ability to provide orthopedic education in formats compatible with the new learning mediums has not been up to the demand, with issues of cost, accessibility, and efficacy plaguing the current process.^3,5 Also, we have yet to unlock the benefits of surgical simulation, which has the potential to provide more effective training at no risk to the patient.^4,13 By adapting to the new learning formats, we can provide numerous new opportunities for keeping up to date on evolving practice management principles, which, with added accessibility, will be used more often by orthopedic surgeons and the public.¹³ 

Research

Research is vital for quality improvement and the continuation of excellence.⁵ It is only with research that we can provide groundbreaking advances and measure the outcomes of our interventions.² Unfortunately, orthopedic research funding continues to be disproportionately low, especially given that musculoskeletal ailments are the leading cause of both physician visits and chronic impairment in the United States.² For example, the National Institute of Arthritis and Musculoskeletal and Skin Diseases receives only 10% of what our country spends on cancer research and 15% of what is spent on heart- and lung-disease research.² To compound the problem of limited funding, the number of physician-scientists has been dropping at an alarming rate.² As a result, we must not only refocus our research efforts so that they are efficient and effective, but we must also invest in the training of orthopedic physician-scientists to ensure a continuous stream of groundbreaking discoveries. We owe it to our patients to provide them with proven, effective, and high-quality care.

Industry Relationships

Local and national attention will continue to focus on our relationships with industry. The challenge is twofold: mitigating the negative portrayal of industry relationships and navigating the changes applied to industry funding for research and education.⁹ Our collaboration with industry is important for the development and advancement of orthopedics,¹⁵ but it must be guided by the professional and ethical guidelines established by the AAOS, ensuring that the best interest of patients remains a top priority.^8,15 We must maintain the public’s trust by using every opportunity to convey our lone goal in collaborating with industry, ie, improving patient care.⁹ According to James Beaty,⁷ any relationship with industry should be “so ethical that it could be printed on the front page of the newspaper and we could face our neighbors with our heads held high.”

Gender and Minority Representation

The racial and ethnic makeup of the United States is undergoing a rapid change. Over the next 4 decades, the white population is projected to become the minority, while women will continue to outnumber men.¹⁶ Despite the rapidly changing demographics of the United States, health care disparities persist. As of 2011, minorities and women made up only 22.55% and 14.52%, respectively, of all orthopedic surgery residents.¹⁷ This limited diversity in orthopedic training programs is alarming and may lead to suboptimal physician–patient relationships, because patients tend to be more comfortable with and respond better to the care provided by physicians of similar background.³ In addition, if we do not integrate women into orthopedics, the number of female medical students applying to orthopedic residency programs might decline.³

Equating excellent medical care with diversity and cultural competence requires that we bridge the gap that has prevented patients from obtaining high-quality care.⁸ To achieve this goal, we need to continue recruiting orthopedic surgeons from all segments of our population. Ultimately, health care disparities can be effectively reduced through the delivery of culturally competent care.⁸

Physician–Patient Relationship

Medical liability has resulted in the development of damaging attitudes among physicians, with many viewing patients as potential adversaries and even avoiding high-risk procedures altogether.⁶ This deterioration of the physician–patient relationship has been another troubling consequence of managed care that emphasizes quantity and speed.¹ As a result, we are perceived by the public as impersonal, poor listeners, and difficult to see on short notice.¹

The poor perception of orthopedic surgeons by the general public is not acceptable for a field that places such a high value on excellence. Patient-centered care is at the core of quality improvement, and improving patient relationships starts and ends with us and with each patient we treat.⁶ In a health care environment in which the average orthopedic surgeon cares for thousands of patients each year, we must make certain to use each opportunity to engage our patients and enhance our relationships with them.⁶ The basic necessities of patient-centered care include empowerment of the patient through education, better communication, and transparency; providing accurate and evidence-based information; and cooperation among physicians.^3,6 The benefits of improving personal relationships with patients are multifold and could have lasting positive effects: increased physician and patient satisfaction, better patient compliance, greater practice efficiency, and fewer malpractice lawsuits.¹ We can also benefit from mobilizing a greater constituency to advocate alongside us.⁶

Unity

Despite accounting for less than 3% of all physicians, orthopedic surgeons have assumed an influential voice in the field of medicine.¹³ This is attributed not only to the success of our interventions but, more importantly, to the fact that we have “stuck together.”¹³ The concept of “sticking together” may seem a cliché and facile but will certainly be a pressing need as we move ahead. We draw strength from the breadth and diversity of our subspecialties, but this strength may become a weakness if we do not join in promoting the betterment of our profession as a whole.¹⁴ To avoid duplications and bring synergy to all our efforts, we should continue to develop new partnerships in our specialty societies⁶ and speak with one voice to our patients and to the public.¹⁵ Joshua Jacobs¹¹ reminds us of the warning Benjamin Franklin imparted to the signers of the Declaration of Independence, “We must hang together, or most assuredly, we will all hang separately.” To ensure the continued strength of the house of orthopedics, we must live by this tenet.

Advocacy

The federal government has become increasingly involved in regulating the practice of medicine.⁹ Orthopedic surgery has been hit especially hard, because the cost of implants and continued innovation has fueled the belief that our profession is a major contributor to unsustainable health care costs.¹¹ We now face multiple legislative regulations related to physician reimbursement, ownership, self-referral, medical liability, and mandates of the Affordable Care Act.⁹ As a result, there has been a decreasing role for orthopedic surgeons as independent practitioners, with more orthopedists forgoing physician-owned practices for large hospital corporations. We are also in increasing competition for limited resources.¹⁰ This is compounded by the fact that those regulating health care, paying for health care, and allocating research funding fail to comprehend the high societal needs for treatment of musculoskeletal diseases and injuries,⁶ which will only increase in the coming decades.¹⁴

The aforementioned challenges make our involvement at all levels of the political process more necessary than ever before.^5,9 E. Anthony Rankin⁸ reminds us, “As physicians, we cannot in good conscience allow our patients’ access to quality orthopedic care to be determined solely by the government, the insurance companies, the trial lawyers, or others…. Either we will have a voice in defining the future of health care, or it will be defined by others for us.” Our advocacy approach, however, should be very careful. Joshua Jacobs¹¹ cautions that “we will be most effective if our advocacy message is presented as a potential solution to the current health care crisis, not just as a demand for fair reimbursement.” Instead, we can achieve this goal with what Richard Gelberman² summarized as “doing what we do best: accumulating knowledge, positioning ourselves as the authorities that we are, and using what we learn to advocate for better patient care and research.”

Value Medicine

Orthopedic surgeons are now expected to provide not just high-quality care but low-cost care. In line with the emerging emphasis on value, sharp focus has been placed on the assessment of physician performance and treatment outcomes as quality-of-care measures.⁶ But how have we measured the quality of the care we provide? We have not, or, at least, we have not had valid or reliable means of doing so.⁶ Gone are the days of telling the world of the excellence of our profession in the treatment of musculoskeletal disease. We now must prove to our patients, the government, and payers that what we do works.^12,13 If we fail to communicate the cost effectiveness of our interventions, our new knowledge and technologies will not be accepted or funded.¹⁰ We should, however, not be discouraged by the new “value equation,” but use it as an incentive to provide evidence-based care and to improve the efficiency of resource utilization.¹⁴ Today, we are urged to be leaders in quality improvement, both in our individual orthopedic practices and as a profession.^10,12,13

Conclusion

Meeting increasingly higher demands for musculoskeletal care in an evolving medical landscape will bring a new set of challenges that will be more frequent and more intense than those in the past.¹⁴ Today, we are tasked with providing fiscally efficient, culturally competent, high-quality, evidence-based, and compassionate care. We are also tasked with reclaiming our ability to shape the future of our profession at the policymaking level. In doing so, the need for unity, advocacy, commitment to education and research, women and minority representation, and open communication with the public has never been more relevant. As we continue to advance as a profession, we must resist the temptation to look back in defiance of change but move forward, confident in our ability to evolve. ◾

Orthopedic surgery is going through a time of remarkable change. Health care reform, heightened public scrutiny, shifting population demographics, increased reliance on the Internet for information, ongoing metamorphosis of our profession into a business, and lack of consistent high-quality clinical evidence have created a new frontier of challenges and opportunities. At heart are the needs to deliver high-quality education that is in line with new technological media, to reclaim our ability to guide musculoskeletal care at the policymaking level, to fortify our long-held tradition of ethical responsibility, to invest in research and the training of physician-scientists, to maintain unity among the different subspecialties, and to increase female and minority representation. Never before has understanding and applying the key tenets of our philosophy as orthopedic surgeons been more crucial.

The changing landscape of orthopedic practice has been an unsettling topic in many of the American Academy of Orthopaedic Surgeons (AAOS) presidential addresses in recent years.^1-11 What are the challenges and what can we learn moving forward? In this article, we seek to answer these questions by drawing insights from the combined experience and wisdom of past AAOS presidents since the turn of the 21st century.

Education

Education is the cornerstone of providing quality musculoskeletal care¹² and staying up to date with technological advances.¹³ The modes of education delivery, however, have changed. No longer is orthopedic education confined to tangible textbooks and journal articles, nor is it limited to those of us in the profession. Instead, orthopedic education has shifted toward online learning¹⁴ and is available to patients and nonorthopedic providers.¹² With more patients gaining access to rapidly growing online resources, a unique challenge has arisen: an abundance of data with variable quality of evidence influencing the decision-making process. This has created what Richard Kyle¹⁵ described as the “trap of the new technology war,” where patient misinformation and direct-to-consumer marketing can lead to dangerous musculoskeletal care delivery, including unrealistic patient expectations.³ To compound the problem, our ability to provide orthopedic education in formats compatible with the new learning mediums has not been up to the demand, with issues of cost, accessibility, and efficacy plaguing the current process.^3,5 Also, we have yet to unlock the benefits of surgical simulation, which has the potential to provide more effective training at no risk to the patient.^4,13 By adapting to the new learning formats, we can provide numerous new opportunities for keeping up to date on evolving practice management principles, which, with added accessibility, will be used more often by orthopedic surgeons and the public.¹³ 

Research

Research is vital for quality improvement and the continuation of excellence.⁵ It is only with research that we can provide groundbreaking advances and measure the outcomes of our interventions.² Unfortunately, orthopedic research funding continues to be disproportionately low, especially given that musculoskeletal ailments are the leading cause of both physician visits and chronic impairment in the United States.² For example, the National Institute of Arthritis and Musculoskeletal and Skin Diseases receives only 10% of what our country spends on cancer research and 15% of what is spent on heart- and lung-disease research.² To compound the problem of limited funding, the number of physician-scientists has been dropping at an alarming rate.² As a result, we must not only refocus our research efforts so that they are efficient and effective, but we must also invest in the training of orthopedic physician-scientists to ensure a continuous stream of groundbreaking discoveries. We owe it to our patients to provide them with proven, effective, and high-quality care.

Industry Relationships

Local and national attention will continue to focus on our relationships with industry. The challenge is twofold: mitigating the negative portrayal of industry relationships and navigating the changes applied to industry funding for research and education.⁹ Our collaboration with industry is important for the development and advancement of orthopedics,¹⁵ but it must be guided by the professional and ethical guidelines established by the AAOS, ensuring that the best interest of patients remains a top priority.^8,15 We must maintain the public’s trust by using every opportunity to convey our lone goal in collaborating with industry, ie, improving patient care.⁹ According to James Beaty,⁷ any relationship with industry should be “so ethical that it could be printed on the front page of the newspaper and we could face our neighbors with our heads held high.”

Gender and Minority Representation

The racial and ethnic makeup of the United States is undergoing a rapid change. Over the next 4 decades, the white population is projected to become the minority, while women will continue to outnumber men.¹⁶ Despite the rapidly changing demographics of the United States, health care disparities persist. As of 2011, minorities and women made up only 22.55% and 14.52%, respectively, of all orthopedic surgery residents.¹⁷ This limited diversity in orthopedic training programs is alarming and may lead to suboptimal physician–patient relationships, because patients tend to be more comfortable with and respond better to the care provided by physicians of similar background.³ In addition, if we do not integrate women into orthopedics, the number of female medical students applying to orthopedic residency programs might decline.³

Equating excellent medical care with diversity and cultural competence requires that we bridge the gap that has prevented patients from obtaining high-quality care.⁸ To achieve this goal, we need to continue recruiting orthopedic surgeons from all segments of our population. Ultimately, health care disparities can be effectively reduced through the delivery of culturally competent care.⁸

Physician–Patient Relationship

Medical liability has resulted in the development of damaging attitudes among physicians, with many viewing patients as potential adversaries and even avoiding high-risk procedures altogether.⁶ This deterioration of the physician–patient relationship has been another troubling consequence of managed care that emphasizes quantity and speed.¹ As a result, we are perceived by the public as impersonal, poor listeners, and difficult to see on short notice.¹

The poor perception of orthopedic surgeons by the general public is not acceptable for a field that places such a high value on excellence. Patient-centered care is at the core of quality improvement, and improving patient relationships starts and ends with us and with each patient we treat.⁶ In a health care environment in which the average orthopedic surgeon cares for thousands of patients each year, we must make certain to use each opportunity to engage our patients and enhance our relationships with them.⁶ The basic necessities of patient-centered care include empowerment of the patient through education, better communication, and transparency; providing accurate and evidence-based information; and cooperation among physicians.^3,6 The benefits of improving personal relationships with patients are multifold and could have lasting positive effects: increased physician and patient satisfaction, better patient compliance, greater practice efficiency, and fewer malpractice lawsuits.¹ We can also benefit from mobilizing a greater constituency to advocate alongside us.⁶

Unity

Despite accounting for less than 3% of all physicians, orthopedic surgeons have assumed an influential voice in the field of medicine.¹³ This is attributed not only to the success of our interventions but, more importantly, to the fact that we have “stuck together.”¹³ The concept of “sticking together” may seem a cliché and facile but will certainly be a pressing need as we move ahead. We draw strength from the breadth and diversity of our subspecialties, but this strength may become a weakness if we do not join in promoting the betterment of our profession as a whole.¹⁴ To avoid duplications and bring synergy to all our efforts, we should continue to develop new partnerships in our specialty societies⁶ and speak with one voice to our patients and to the public.¹⁵ Joshua Jacobs¹¹ reminds us of the warning Benjamin Franklin imparted to the signers of the Declaration of Independence, “We must hang together, or most assuredly, we will all hang separately.” To ensure the continued strength of the house of orthopedics, we must live by this tenet.

Advocacy

The federal government has become increasingly involved in regulating the practice of medicine.⁹ Orthopedic surgery has been hit especially hard, because the cost of implants and continued innovation has fueled the belief that our profession is a major contributor to unsustainable health care costs.¹¹ We now face multiple legislative regulations related to physician reimbursement, ownership, self-referral, medical liability, and mandates of the Affordable Care Act.⁹ As a result, there has been a decreasing role for orthopedic surgeons as independent practitioners, with more orthopedists forgoing physician-owned practices for large hospital corporations. We are also in increasing competition for limited resources.¹⁰ This is compounded by the fact that those regulating health care, paying for health care, and allocating research funding fail to comprehend the high societal needs for treatment of musculoskeletal diseases and injuries,⁶ which will only increase in the coming decades.¹⁴

The aforementioned challenges make our involvement at all levels of the political process more necessary than ever before.^5,9 E. Anthony Rankin⁸ reminds us, “As physicians, we cannot in good conscience allow our patients’ access to quality orthopedic care to be determined solely by the government, the insurance companies, the trial lawyers, or others…. Either we will have a voice in defining the future of health care, or it will be defined by others for us.” Our advocacy approach, however, should be very careful. Joshua Jacobs¹¹ cautions that “we will be most effective if our advocacy message is presented as a potential solution to the current health care crisis, not just as a demand for fair reimbursement.” Instead, we can achieve this goal with what Richard Gelberman² summarized as “doing what we do best: accumulating knowledge, positioning ourselves as the authorities that we are, and using what we learn to advocate for better patient care and research.”

Value Medicine

Orthopedic surgeons are now expected to provide not just high-quality care but low-cost care. In line with the emerging emphasis on value, sharp focus has been placed on the assessment of physician performance and treatment outcomes as quality-of-care measures.⁶ But how have we measured the quality of the care we provide? We have not, or, at least, we have not had valid or reliable means of doing so.⁶ Gone are the days of telling the world of the excellence of our profession in the treatment of musculoskeletal disease. We now must prove to our patients, the government, and payers that what we do works.^12,13 If we fail to communicate the cost effectiveness of our interventions, our new knowledge and technologies will not be accepted or funded.¹⁰ We should, however, not be discouraged by the new “value equation,” but use it as an incentive to provide evidence-based care and to improve the efficiency of resource utilization.¹⁴ Today, we are urged to be leaders in quality improvement, both in our individual orthopedic practices and as a profession.^10,12,13

Conclusion

Meeting increasingly higher demands for musculoskeletal care in an evolving medical landscape will bring a new set of challenges that will be more frequent and more intense than those in the past.¹⁴ Today, we are tasked with providing fiscally efficient, culturally competent, high-quality, evidence-based, and compassionate care. We are also tasked with reclaiming our ability to shape the future of our profession at the policymaking level. In doing so, the need for unity, advocacy, commitment to education and research, women and minority representation, and open communication with the public has never been more relevant. As we continue to advance as a profession, we must resist the temptation to look back in defiance of change but move forward, confident in our ability to evolve. ◾

Orthopedic surgery is going through a time of remarkable change. Health care reform, heightened public scrutiny, shifting population demographics, increased reliance on the Internet for information, ongoing metamorphosis of our profession into a business, and lack of consistent high-quality clinical evidence have created a new frontier of challenges and opportunities. At heart are the needs to deliver high-quality education that is in line with new technological media, to reclaim our ability to guide musculoskeletal care at the policymaking level, to fortify our long-held tradition of ethical responsibility, to invest in research and the training of physician-scientists, to maintain unity among the different subspecialties, and to increase female and minority representation. Never before has understanding and applying the key tenets of our philosophy as orthopedic surgeons been more crucial.

The changing landscape of orthopedic practice has been an unsettling topic in many of the American Academy of Orthopaedic Surgeons (AAOS) presidential addresses in recent years.^1-11 What are the challenges and what can we learn moving forward? In this article, we seek to answer these questions by drawing insights from the combined experience and wisdom of past AAOS presidents since the turn of the 21st century.

Education

Education is the cornerstone of providing quality musculoskeletal care¹² and staying up to date with technological advances.¹³ The modes of education delivery, however, have changed. No longer is orthopedic education confined to tangible textbooks and journal articles, nor is it limited to those of us in the profession. Instead, orthopedic education has shifted toward online learning¹⁴ and is available to patients and nonorthopedic providers.¹² With more patients gaining access to rapidly growing online resources, a unique challenge has arisen: an abundance of data with variable quality of evidence influencing the decision-making process. This has created what Richard Kyle¹⁵ described as the “trap of the new technology war,” where patient misinformation and direct-to-consumer marketing can lead to dangerous musculoskeletal care delivery, including unrealistic patient expectations.³ To compound the problem, our ability to provide orthopedic education in formats compatible with the new learning mediums has not been up to the demand, with issues of cost, accessibility, and efficacy plaguing the current process.^3,5 Also, we have yet to unlock the benefits of surgical simulation, which has the potential to provide more effective training at no risk to the patient.^4,13 By adapting to the new learning formats, we can provide numerous new opportunities for keeping up to date on evolving practice management principles, which, with added accessibility, will be used more often by orthopedic surgeons and the public.¹³ 

Research

Research is vital for quality improvement and the continuation of excellence.⁵ It is only with research that we can provide groundbreaking advances and measure the outcomes of our interventions.² Unfortunately, orthopedic research funding continues to be disproportionately low, especially given that musculoskeletal ailments are the leading cause of both physician visits and chronic impairment in the United States.² For example, the National Institute of Arthritis and Musculoskeletal and Skin Diseases receives only 10% of what our country spends on cancer research and 15% of what is spent on heart- and lung-disease research.² To compound the problem of limited funding, the number of physician-scientists has been dropping at an alarming rate.² As a result, we must not only refocus our research efforts so that they are efficient and effective, but we must also invest in the training of orthopedic physician-scientists to ensure a continuous stream of groundbreaking discoveries. We owe it to our patients to provide them with proven, effective, and high-quality care.

Industry Relationships

Local and national attention will continue to focus on our relationships with industry. The challenge is twofold: mitigating the negative portrayal of industry relationships and navigating the changes applied to industry funding for research and education.⁹ Our collaboration with industry is important for the development and advancement of orthopedics,¹⁵ but it must be guided by the professional and ethical guidelines established by the AAOS, ensuring that the best interest of patients remains a top priority.^8,15 We must maintain the public’s trust by using every opportunity to convey our lone goal in collaborating with industry, ie, improving patient care.⁹ According to James Beaty,⁷ any relationship with industry should be “so ethical that it could be printed on the front page of the newspaper and we could face our neighbors with our heads held high.”

Gender and Minority Representation

The racial and ethnic makeup of the United States is undergoing a rapid change. Over the next 4 decades, the white population is projected to become the minority, while women will continue to outnumber men.¹⁶ Despite the rapidly changing demographics of the United States, health care disparities persist. As of 2011, minorities and women made up only 22.55% and 14.52%, respectively, of all orthopedic surgery residents.¹⁷ This limited diversity in orthopedic training programs is alarming and may lead to suboptimal physician–patient relationships, because patients tend to be more comfortable with and respond better to the care provided by physicians of similar background.³ In addition, if we do not integrate women into orthopedics, the number of female medical students applying to orthopedic residency programs might decline.³

Equating excellent medical care with diversity and cultural competence requires that we bridge the gap that has prevented patients from obtaining high-quality care.⁸ To achieve this goal, we need to continue recruiting orthopedic surgeons from all segments of our population. Ultimately, health care disparities can be effectively reduced through the delivery of culturally competent care.⁸

Physician–Patient Relationship

Medical liability has resulted in the development of damaging attitudes among physicians, with many viewing patients as potential adversaries and even avoiding high-risk procedures altogether.⁶ This deterioration of the physician–patient relationship has been another troubling consequence of managed care that emphasizes quantity and speed.¹ As a result, we are perceived by the public as impersonal, poor listeners, and difficult to see on short notice.¹

The poor perception of orthopedic surgeons by the general public is not acceptable for a field that places such a high value on excellence. Patient-centered care is at the core of quality improvement, and improving patient relationships starts and ends with us and with each patient we treat.⁶ In a health care environment in which the average orthopedic surgeon cares for thousands of patients each year, we must make certain to use each opportunity to engage our patients and enhance our relationships with them.⁶ The basic necessities of patient-centered care include empowerment of the patient through education, better communication, and transparency; providing accurate and evidence-based information; and cooperation among physicians.^3,6 The benefits of improving personal relationships with patients are multifold and could have lasting positive effects: increased physician and patient satisfaction, better patient compliance, greater practice efficiency, and fewer malpractice lawsuits.¹ We can also benefit from mobilizing a greater constituency to advocate alongside us.⁶

Unity

Despite accounting for less than 3% of all physicians, orthopedic surgeons have assumed an influential voice in the field of medicine.¹³ This is attributed not only to the success of our interventions but, more importantly, to the fact that we have “stuck together.”¹³ The concept of “sticking together” may seem a cliché and facile but will certainly be a pressing need as we move ahead. We draw strength from the breadth and diversity of our subspecialties, but this strength may become a weakness if we do not join in promoting the betterment of our profession as a whole.¹⁴ To avoid duplications and bring synergy to all our efforts, we should continue to develop new partnerships in our specialty societies⁶ and speak with one voice to our patients and to the public.¹⁵ Joshua Jacobs¹¹ reminds us of the warning Benjamin Franklin imparted to the signers of the Declaration of Independence, “We must hang together, or most assuredly, we will all hang separately.” To ensure the continued strength of the house of orthopedics, we must live by this tenet.

Advocacy

The federal government has become increasingly involved in regulating the practice of medicine.⁹ Orthopedic surgery has been hit especially hard, because the cost of implants and continued innovation has fueled the belief that our profession is a major contributor to unsustainable health care costs.¹¹ We now face multiple legislative regulations related to physician reimbursement, ownership, self-referral, medical liability, and mandates of the Affordable Care Act.⁹ As a result, there has been a decreasing role for orthopedic surgeons as independent practitioners, with more orthopedists forgoing physician-owned practices for large hospital corporations. We are also in increasing competition for limited resources.¹⁰ This is compounded by the fact that those regulating health care, paying for health care, and allocating research funding fail to comprehend the high societal needs for treatment of musculoskeletal diseases and injuries,⁶ which will only increase in the coming decades.¹⁴

The aforementioned challenges make our involvement at all levels of the political process more necessary than ever before.^5,9 E. Anthony Rankin⁸ reminds us, “As physicians, we cannot in good conscience allow our patients’ access to quality orthopedic care to be determined solely by the government, the insurance companies, the trial lawyers, or others…. Either we will have a voice in defining the future of health care, or it will be defined by others for us.” Our advocacy approach, however, should be very careful. Joshua Jacobs¹¹ cautions that “we will be most effective if our advocacy message is presented as a potential solution to the current health care crisis, not just as a demand for fair reimbursement.” Instead, we can achieve this goal with what Richard Gelberman² summarized as “doing what we do best: accumulating knowledge, positioning ourselves as the authorities that we are, and using what we learn to advocate for better patient care and research.”

Value Medicine

Orthopedic surgeons are now expected to provide not just high-quality care but low-cost care. In line with the emerging emphasis on value, sharp focus has been placed on the assessment of physician performance and treatment outcomes as quality-of-care measures.⁶ But how have we measured the quality of the care we provide? We have not, or, at least, we have not had valid or reliable means of doing so.⁶ Gone are the days of telling the world of the excellence of our profession in the treatment of musculoskeletal disease. We now must prove to our patients, the government, and payers that what we do works.^12,13 If we fail to communicate the cost effectiveness of our interventions, our new knowledge and technologies will not be accepted or funded.¹⁰ We should, however, not be discouraged by the new “value equation,” but use it as an incentive to provide evidence-based care and to improve the efficiency of resource utilization.¹⁴ Today, we are urged to be leaders in quality improvement, both in our individual orthopedic practices and as a profession.^10,12,13

Conclusion

Meeting increasingly higher demands for musculoskeletal care in an evolving medical landscape will bring a new set of challenges that will be more frequent and more intense than those in the past.¹⁴ Today, we are tasked with providing fiscally efficient, culturally competent, high-quality, evidence-based, and compassionate care. We are also tasked with reclaiming our ability to shape the future of our profession at the policymaking level. In doing so, the need for unity, advocacy, commitment to education and research, women and minority representation, and open communication with the public has never been more relevant. As we continue to advance as a profession, we must resist the temptation to look back in defiance of change but move forward, confident in our ability to evolve. ◾

Spondylolysis is a bone defect of the pars interarticularis. It is usually seen in adolescents who participate in sporting activities that involve repetitive axial loads to a hyperextended lower back, such as football offensive lineman, throwing athletes, and gymnasts. It occurs frequently in the L5 pars and can be unilateral or bilateral. The majority of reported multiple-level spondylolysis is at consecutive lumbar segments.^1-6 Rarely, it affects noncontiguous levels. Most patients respond well to conservative treatment in the form of activity modification and orthosis.⁷ Surgical intervention is considered if 6 months of conservative management fails, spondylolisthesis develops, or intractable neurologic symptoms arise.

This case report presents an 18-year-old man with noncontiguous spondylolysis at L2 and L5 who was successfully treated with a 1-level pars repair at L2 after failed conservative management. This unique case highlights the importance of using single-photon emission computed tomography (SPECT) scan and diagnostic pars block when planning for surgical treatment in the rare cases of noncontiguous spondylolysis. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

An 18-year-old man presented to the clinic with worsening lower back pain for the previous 4 weeks. He was playing high school baseball and stated the pain was worse when he swung his bat. He had no history of trauma or back pain. Rest was the only alleviating factor, and he was beginning to experience pain when he stood after sitting. He denied any radicular pain. On examination, he had midline tenderness along the upper lumbar spine and pain with lumbar spine extension. His neurologic examination showed normal sensation with 5/5 strength in all key muscle groups. Plain radiograph of the lumbar spine showed an L5 pars defect (Figures 1A, 1B). A SPECT scan showed increased uptake at L2 pars bilaterally; the L5 pars did not show increased uptake (Figures 2A, 2B). A computed tomography (CT) scan confirmed bilateral L2 pars fractures and a left L5 pars fracture (Figures 3A, 3B). Bony changes in the form of marginal sclerosis at the L5, but not the L2, pars suggested that the L2 fracture was acute while the L5 fracture was chronic (Figures 4A, 4B).

The patient had conservative management for 6 months in the form of lumbosacral orthosis (LSO), cessation of sports activities, and physical therapy. The patient was initially treated with an LSO brace for 3 months, after which he had physical therapy. At 6 month follow-up, he reported continuing, significant back pain. A repeat CT scan of the lumbar spine showed no interval healing of the bilateral L2 or the unilateral L5 pars fractures. As a result of the patient’s noncontiguous pars fractures, a diagnostic CT-guided block of L2 pars was performed to identify which level was his main pain generator (Figure 5). He reported a brief period of complete pain relief after the L2 pars block. With failure of 6 months’ conservative management and positive SPECT scan and diagnostic block, surgical treatment was recommended. Prior to surgical intervention, magnetic resonance imaging was obtained to rule out pathology (eg, disc degeneration, infection, or tumor) other than the pars defect that could require fusion instead of pars repair (Figures 6A, 6B). Because of the patient’s young age, bilateral L2 pars repair rather than fusion was indicated. After 8 months of persistent back pain, he underwent bilateral L2 pars repair with iliac crest autograft, pedicle screws, and sublaminar hook fixation (Figures 7A, 7B). The patient had an uneventful immediate postoperative course. A 6-month postoperative CT scan showed bridging callus at the L2 pars; however, the left L5 pars fracture was still visible (Figures 8A-8C). Over a 6-month postoperative period, the patient had continued improvement in his back pain, advanced his activity as tolerated without problem, and was allowed to resume his sports activities. At 2-year follow-up, he was playing baseball and basketball, and denied any back pain. 

Discussion

Lumbar spondylolysis is commonly seen at the fourth and fifth lumbar vertebrae, and accounts for more than 95% of spondylolysis cases.⁸ Multiple-level spondylolysis is a relatively rare finding with an incidence varying between 1.2% and 5.6%. The majority of the reported multiple-level cases are adjacent.^1-3,6 Adolescents often present with a history of insidious-onset low back pain without radicular symptoms that is exacerbated by activity. Occasionally, an acute injury may elicit the onset of pain. A thorough history with emphasis on pain in relation to activity and sports involvement is beneficial. The patient in the current study was a throwing athlete and presented with 4 weeks of back pain that worsened with activity; he had no history of trauma.

Radiographic assessment using standing anteroposterior, lateral, and oblique radiographs of the thoracolumbar spine is useful in the initial assessment. A SPECT scan of the lumbosacral spine is highly sensitive for identifying spondylolytic defects when plain radiographs are within normal limits, yet a high index of suspicion remains given the patient’s history and physical examination findings.^9,10 Increased radionuclide uptake within the pars indicates a stress reaction and, possibly, a more acute pathology. The plain radiographs of the patient showed only L5 spondylolysis. However, a SPECT scan showed only increased uptake in L2 pars on both sides. These findings suggested chronic L5 and acute L2 pars defects. A thin-cut CT scan gives the best visualization of pars defect and can help in differentiating chronic defect with sclerotic margins versus acute defect with hazy irregular margins. In the current case, the CT scan showed changes consistent with unilateral chronic L5 and bilateral acute L2 pars defects.

The origin of the pain in spondylolysis is from the tissues rich in nociceptive nerve endings in the loose posterior arch. A CT-guided pars block is a very useful diagnostic preoperative tool that confirms the symptomatic level in cases of multilevel pars defect, especially if they are noncontiguous. In this case, the diagnostic preoperative bilateral L2 pars block confirmed that the pain generator was the acute L2 rather than the chronic L5 pars defect. This step assured that surgical treatment involving only the L2 level would be beneficial in alleviating the patient’s back pain after the failure of 6 months of conservative treatment.

Most patients with single-level spondylolysis respond to conservative treatment, especially after early diagnosis and treatment. The traditional nonoperative treatment of children and adolescents with a symptomatic spondylolytic lesion was a period of rest and progressive increased activity with physical therapy. Immobilization with an LSO was reserved for individuals who did not respond to rest and physical therapy.¹¹ However, multiple studies revealed early immobilization achieved results superior to activity restriction alone, and individuals who underwent a period of activity restriction prior to bracing were more likely to experience persistent symptoms.^12-14 Our patient underwent conservative treatment for 6 months, in the form of LSO, cessation of sport activities, and physical therapy, which failed to give him relief of his back pain.

Surgical intervention is warranted for adolescents with persistent, debilitating pain intractable to at least a 6-month period of nonoperative management. Additional indications for surgical management are those individuals who present with neurologic deficits and isthmic spondylolisthesis. Surgical treatment involves direct pars repair with iliac crest bone graft and use of a sublaminar hook/pedicle screw construct, cerclage wire, or pars screw.^15-18 

In contrast to single-level pars defects that respond well to conservative treatment, there are conflicting reports regarding the management of multiple-level pars fractures; a few reports suggest good outcome with conservative management, but the majority state that surgery is often required and conservative measures are rarely useful.^1-4,6 Nayeemuddin and colleagues¹⁹ reported a case of a 16-year-old football player who presented with a 4-month history of constant low back pain related to bilateral L3 and L5 pars defects that responded to 1 year of conservative management, when the more acute fractures at L3 showed complete bony union and the patient had symptomatic pain relief and was able to return to full sporting activity.

 Chang and colleagues² reported 10 patients with adjacent 2-level bilateral spondylolysis treated successfully using a pedicle screw–hook construct with autogenous bone grafting. Ogawa and colleagues⁵ reported adjacent 2-level spondylolysis in 5 patients and 3-level spondylolysis in 2 patients, who were treated successfully by segmental wire fixation and bone grafting. Ivanic and colleagues¹⁵ retrospectively reviewed 113 patients with spondylolysis who were treated with direct repair using a hook-screw construct and showed a pseudoarthrosis rate of 13.3%. Superior fusion rates were observed in patients 14 years and younger compared with older patients, particularly those 20 years and older.¹⁵ Roca and colleagues¹⁶ prospectively analyzed 19 consecutive cases of spondylolysis that were repaired using a hook-screw construct. Twelve of 13 patients (92%) who were 20 years or younger at the time of the study (average age, 17.2 years) had fusion, whereas, in 6 patients 21 years and older (average age, 27.5 years), no cases of fusion were observed. The patients 20 years or younger had significantly better clinical results than those obtained in the patients 21 years and older. The authors concluded that pedicle screw–hook fixation is a useful alternative in the treatment of spondylolysis in adolescents, but did not recommend this procedure in patients older than 20 years.¹⁶

Conclusion

The current case demonstrates a unique example of rare noncontiguous pars defects successfully treated with primary repair of 1 level when conservative management failed and the symptomatic defect was isolated. It also highlights the importance of investigating the entirety of the lumbar spine when diagnosis of L5 spondylolysis rules out noncontiguous pars defects. The treatment of noncontiguous pars defects is not well defined; this case showed the importance of using a SPECT scan and a diagnostic pars block to help isolate the symptomatic level when surgical management is considered after a failure of conservative treatment. This case shows 2 possible results: the chronic unilateral L5 defect responded to nonsurgical treatment with asymptomatic fibrous nonunion, while the more acute bilateral L2 defect responded to pars repair with pedicle screw–hook fixation and iliac crest bone graft. 

Spondylolysis is a bone defect of the pars interarticularis. It is usually seen in adolescents who participate in sporting activities that involve repetitive axial loads to a hyperextended lower back, such as football offensive lineman, throwing athletes, and gymnasts. It occurs frequently in the L5 pars and can be unilateral or bilateral. The majority of reported multiple-level spondylolysis is at consecutive lumbar segments.^1-6 Rarely, it affects noncontiguous levels. Most patients respond well to conservative treatment in the form of activity modification and orthosis.⁷ Surgical intervention is considered if 6 months of conservative management fails, spondylolisthesis develops, or intractable neurologic symptoms arise.

This case report presents an 18-year-old man with noncontiguous spondylolysis at L2 and L5 who was successfully treated with a 1-level pars repair at L2 after failed conservative management. This unique case highlights the importance of using single-photon emission computed tomography (SPECT) scan and diagnostic pars block when planning for surgical treatment in the rare cases of noncontiguous spondylolysis. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

An 18-year-old man presented to the clinic with worsening lower back pain for the previous 4 weeks. He was playing high school baseball and stated the pain was worse when he swung his bat. He had no history of trauma or back pain. Rest was the only alleviating factor, and he was beginning to experience pain when he stood after sitting. He denied any radicular pain. On examination, he had midline tenderness along the upper lumbar spine and pain with lumbar spine extension. His neurologic examination showed normal sensation with 5/5 strength in all key muscle groups. Plain radiograph of the lumbar spine showed an L5 pars defect (Figures 1A, 1B). A SPECT scan showed increased uptake at L2 pars bilaterally; the L5 pars did not show increased uptake (Figures 2A, 2B). A computed tomography (CT) scan confirmed bilateral L2 pars fractures and a left L5 pars fracture (Figures 3A, 3B). Bony changes in the form of marginal sclerosis at the L5, but not the L2, pars suggested that the L2 fracture was acute while the L5 fracture was chronic (Figures 4A, 4B).

The patient had conservative management for 6 months in the form of lumbosacral orthosis (LSO), cessation of sports activities, and physical therapy. The patient was initially treated with an LSO brace for 3 months, after which he had physical therapy. At 6 month follow-up, he reported continuing, significant back pain. A repeat CT scan of the lumbar spine showed no interval healing of the bilateral L2 or the unilateral L5 pars fractures. As a result of the patient’s noncontiguous pars fractures, a diagnostic CT-guided block of L2 pars was performed to identify which level was his main pain generator (Figure 5). He reported a brief period of complete pain relief after the L2 pars block. With failure of 6 months’ conservative management and positive SPECT scan and diagnostic block, surgical treatment was recommended. Prior to surgical intervention, magnetic resonance imaging was obtained to rule out pathology (eg, disc degeneration, infection, or tumor) other than the pars defect that could require fusion instead of pars repair (Figures 6A, 6B). Because of the patient’s young age, bilateral L2 pars repair rather than fusion was indicated. After 8 months of persistent back pain, he underwent bilateral L2 pars repair with iliac crest autograft, pedicle screws, and sublaminar hook fixation (Figures 7A, 7B). The patient had an uneventful immediate postoperative course. A 6-month postoperative CT scan showed bridging callus at the L2 pars; however, the left L5 pars fracture was still visible (Figures 8A-8C). Over a 6-month postoperative period, the patient had continued improvement in his back pain, advanced his activity as tolerated without problem, and was allowed to resume his sports activities. At 2-year follow-up, he was playing baseball and basketball, and denied any back pain. 

Discussion

Lumbar spondylolysis is commonly seen at the fourth and fifth lumbar vertebrae, and accounts for more than 95% of spondylolysis cases.⁸ Multiple-level spondylolysis is a relatively rare finding with an incidence varying between 1.2% and 5.6%. The majority of the reported multiple-level cases are adjacent.^1-3,6 Adolescents often present with a history of insidious-onset low back pain without radicular symptoms that is exacerbated by activity. Occasionally, an acute injury may elicit the onset of pain. A thorough history with emphasis on pain in relation to activity and sports involvement is beneficial. The patient in the current study was a throwing athlete and presented with 4 weeks of back pain that worsened with activity; he had no history of trauma.

Radiographic assessment using standing anteroposterior, lateral, and oblique radiographs of the thoracolumbar spine is useful in the initial assessment. A SPECT scan of the lumbosacral spine is highly sensitive for identifying spondylolytic defects when plain radiographs are within normal limits, yet a high index of suspicion remains given the patient’s history and physical examination findings.^9,10 Increased radionuclide uptake within the pars indicates a stress reaction and, possibly, a more acute pathology. The plain radiographs of the patient showed only L5 spondylolysis. However, a SPECT scan showed only increased uptake in L2 pars on both sides. These findings suggested chronic L5 and acute L2 pars defects. A thin-cut CT scan gives the best visualization of pars defect and can help in differentiating chronic defect with sclerotic margins versus acute defect with hazy irregular margins. In the current case, the CT scan showed changes consistent with unilateral chronic L5 and bilateral acute L2 pars defects.

The origin of the pain in spondylolysis is from the tissues rich in nociceptive nerve endings in the loose posterior arch. A CT-guided pars block is a very useful diagnostic preoperative tool that confirms the symptomatic level in cases of multilevel pars defect, especially if they are noncontiguous. In this case, the diagnostic preoperative bilateral L2 pars block confirmed that the pain generator was the acute L2 rather than the chronic L5 pars defect. This step assured that surgical treatment involving only the L2 level would be beneficial in alleviating the patient’s back pain after the failure of 6 months of conservative treatment.

Most patients with single-level spondylolysis respond to conservative treatment, especially after early diagnosis and treatment. The traditional nonoperative treatment of children and adolescents with a symptomatic spondylolytic lesion was a period of rest and progressive increased activity with physical therapy. Immobilization with an LSO was reserved for individuals who did not respond to rest and physical therapy.¹¹ However, multiple studies revealed early immobilization achieved results superior to activity restriction alone, and individuals who underwent a period of activity restriction prior to bracing were more likely to experience persistent symptoms.^12-14 Our patient underwent conservative treatment for 6 months, in the form of LSO, cessation of sport activities, and physical therapy, which failed to give him relief of his back pain.

Surgical intervention is warranted for adolescents with persistent, debilitating pain intractable to at least a 6-month period of nonoperative management. Additional indications for surgical management are those individuals who present with neurologic deficits and isthmic spondylolisthesis. Surgical treatment involves direct pars repair with iliac crest bone graft and use of a sublaminar hook/pedicle screw construct, cerclage wire, or pars screw.^15-18 

In contrast to single-level pars defects that respond well to conservative treatment, there are conflicting reports regarding the management of multiple-level pars fractures; a few reports suggest good outcome with conservative management, but the majority state that surgery is often required and conservative measures are rarely useful.^1-4,6 Nayeemuddin and colleagues¹⁹ reported a case of a 16-year-old football player who presented with a 4-month history of constant low back pain related to bilateral L3 and L5 pars defects that responded to 1 year of conservative management, when the more acute fractures at L3 showed complete bony union and the patient had symptomatic pain relief and was able to return to full sporting activity.

 Chang and colleagues² reported 10 patients with adjacent 2-level bilateral spondylolysis treated successfully using a pedicle screw–hook construct with autogenous bone grafting. Ogawa and colleagues⁵ reported adjacent 2-level spondylolysis in 5 patients and 3-level spondylolysis in 2 patients, who were treated successfully by segmental wire fixation and bone grafting. Ivanic and colleagues¹⁵ retrospectively reviewed 113 patients with spondylolysis who were treated with direct repair using a hook-screw construct and showed a pseudoarthrosis rate of 13.3%. Superior fusion rates were observed in patients 14 years and younger compared with older patients, particularly those 20 years and older.¹⁵ Roca and colleagues¹⁶ prospectively analyzed 19 consecutive cases of spondylolysis that were repaired using a hook-screw construct. Twelve of 13 patients (92%) who were 20 years or younger at the time of the study (average age, 17.2 years) had fusion, whereas, in 6 patients 21 years and older (average age, 27.5 years), no cases of fusion were observed. The patients 20 years or younger had significantly better clinical results than those obtained in the patients 21 years and older. The authors concluded that pedicle screw–hook fixation is a useful alternative in the treatment of spondylolysis in adolescents, but did not recommend this procedure in patients older than 20 years.¹⁶

Conclusion

The current case demonstrates a unique example of rare noncontiguous pars defects successfully treated with primary repair of 1 level when conservative management failed and the symptomatic defect was isolated. It also highlights the importance of investigating the entirety of the lumbar spine when diagnosis of L5 spondylolysis rules out noncontiguous pars defects. The treatment of noncontiguous pars defects is not well defined; this case showed the importance of using a SPECT scan and a diagnostic pars block to help isolate the symptomatic level when surgical management is considered after a failure of conservative treatment. This case shows 2 possible results: the chronic unilateral L5 defect responded to nonsurgical treatment with asymptomatic fibrous nonunion, while the more acute bilateral L2 defect responded to pars repair with pedicle screw–hook fixation and iliac crest bone graft. 

Spondylolysis is a bone defect of the pars interarticularis. It is usually seen in adolescents who participate in sporting activities that involve repetitive axial loads to a hyperextended lower back, such as football offensive lineman, throwing athletes, and gymnasts. It occurs frequently in the L5 pars and can be unilateral or bilateral. The majority of reported multiple-level spondylolysis is at consecutive lumbar segments.^1-6 Rarely, it affects noncontiguous levels. Most patients respond well to conservative treatment in the form of activity modification and orthosis.⁷ Surgical intervention is considered if 6 months of conservative management fails, spondylolisthesis develops, or intractable neurologic symptoms arise.

This case report presents an 18-year-old man with noncontiguous spondylolysis at L2 and L5 who was successfully treated with a 1-level pars repair at L2 after failed conservative management. This unique case highlights the importance of using single-photon emission computed tomography (SPECT) scan and diagnostic pars block when planning for surgical treatment in the rare cases of noncontiguous spondylolysis. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

An 18-year-old man presented to the clinic with worsening lower back pain for the previous 4 weeks. He was playing high school baseball and stated the pain was worse when he swung his bat. He had no history of trauma or back pain. Rest was the only alleviating factor, and he was beginning to experience pain when he stood after sitting. He denied any radicular pain. On examination, he had midline tenderness along the upper lumbar spine and pain with lumbar spine extension. His neurologic examination showed normal sensation with 5/5 strength in all key muscle groups. Plain radiograph of the lumbar spine showed an L5 pars defect (Figures 1A, 1B). A SPECT scan showed increased uptake at L2 pars bilaterally; the L5 pars did not show increased uptake (Figures 2A, 2B). A computed tomography (CT) scan confirmed bilateral L2 pars fractures and a left L5 pars fracture (Figures 3A, 3B). Bony changes in the form of marginal sclerosis at the L5, but not the L2, pars suggested that the L2 fracture was acute while the L5 fracture was chronic (Figures 4A, 4B).

The patient had conservative management for 6 months in the form of lumbosacral orthosis (LSO), cessation of sports activities, and physical therapy. The patient was initially treated with an LSO brace for 3 months, after which he had physical therapy. At 6 month follow-up, he reported continuing, significant back pain. A repeat CT scan of the lumbar spine showed no interval healing of the bilateral L2 or the unilateral L5 pars fractures. As a result of the patient’s noncontiguous pars fractures, a diagnostic CT-guided block of L2 pars was performed to identify which level was his main pain generator (Figure 5). He reported a brief period of complete pain relief after the L2 pars block. With failure of 6 months’ conservative management and positive SPECT scan and diagnostic block, surgical treatment was recommended. Prior to surgical intervention, magnetic resonance imaging was obtained to rule out pathology (eg, disc degeneration, infection, or tumor) other than the pars defect that could require fusion instead of pars repair (Figures 6A, 6B). Because of the patient’s young age, bilateral L2 pars repair rather than fusion was indicated. After 8 months of persistent back pain, he underwent bilateral L2 pars repair with iliac crest autograft, pedicle screws, and sublaminar hook fixation (Figures 7A, 7B). The patient had an uneventful immediate postoperative course. A 6-month postoperative CT scan showed bridging callus at the L2 pars; however, the left L5 pars fracture was still visible (Figures 8A-8C). Over a 6-month postoperative period, the patient had continued improvement in his back pain, advanced his activity as tolerated without problem, and was allowed to resume his sports activities. At 2-year follow-up, he was playing baseball and basketball, and denied any back pain. 

Discussion

Lumbar spondylolysis is commonly seen at the fourth and fifth lumbar vertebrae, and accounts for more than 95% of spondylolysis cases.⁸ Multiple-level spondylolysis is a relatively rare finding with an incidence varying between 1.2% and 5.6%. The majority of the reported multiple-level cases are adjacent.^1-3,6 Adolescents often present with a history of insidious-onset low back pain without radicular symptoms that is exacerbated by activity. Occasionally, an acute injury may elicit the onset of pain. A thorough history with emphasis on pain in relation to activity and sports involvement is beneficial. The patient in the current study was a throwing athlete and presented with 4 weeks of back pain that worsened with activity; he had no history of trauma.

Radiographic assessment using standing anteroposterior, lateral, and oblique radiographs of the thoracolumbar spine is useful in the initial assessment. A SPECT scan of the lumbosacral spine is highly sensitive for identifying spondylolytic defects when plain radiographs are within normal limits, yet a high index of suspicion remains given the patient’s history and physical examination findings.^9,10 Increased radionuclide uptake within the pars indicates a stress reaction and, possibly, a more acute pathology. The plain radiographs of the patient showed only L5 spondylolysis. However, a SPECT scan showed only increased uptake in L2 pars on both sides. These findings suggested chronic L5 and acute L2 pars defects. A thin-cut CT scan gives the best visualization of pars defect and can help in differentiating chronic defect with sclerotic margins versus acute defect with hazy irregular margins. In the current case, the CT scan showed changes consistent with unilateral chronic L5 and bilateral acute L2 pars defects.

The origin of the pain in spondylolysis is from the tissues rich in nociceptive nerve endings in the loose posterior arch. A CT-guided pars block is a very useful diagnostic preoperative tool that confirms the symptomatic level in cases of multilevel pars defect, especially if they are noncontiguous. In this case, the diagnostic preoperative bilateral L2 pars block confirmed that the pain generator was the acute L2 rather than the chronic L5 pars defect. This step assured that surgical treatment involving only the L2 level would be beneficial in alleviating the patient’s back pain after the failure of 6 months of conservative treatment.

Most patients with single-level spondylolysis respond to conservative treatment, especially after early diagnosis and treatment. The traditional nonoperative treatment of children and adolescents with a symptomatic spondylolytic lesion was a period of rest and progressive increased activity with physical therapy. Immobilization with an LSO was reserved for individuals who did not respond to rest and physical therapy.¹¹ However, multiple studies revealed early immobilization achieved results superior to activity restriction alone, and individuals who underwent a period of activity restriction prior to bracing were more likely to experience persistent symptoms.^12-14 Our patient underwent conservative treatment for 6 months, in the form of LSO, cessation of sport activities, and physical therapy, which failed to give him relief of his back pain.

Surgical intervention is warranted for adolescents with persistent, debilitating pain intractable to at least a 6-month period of nonoperative management. Additional indications for surgical management are those individuals who present with neurologic deficits and isthmic spondylolisthesis. Surgical treatment involves direct pars repair with iliac crest bone graft and use of a sublaminar hook/pedicle screw construct, cerclage wire, or pars screw.^15-18 

In contrast to single-level pars defects that respond well to conservative treatment, there are conflicting reports regarding the management of multiple-level pars fractures; a few reports suggest good outcome with conservative management, but the majority state that surgery is often required and conservative measures are rarely useful.^1-4,6 Nayeemuddin and colleagues¹⁹ reported a case of a 16-year-old football player who presented with a 4-month history of constant low back pain related to bilateral L3 and L5 pars defects that responded to 1 year of conservative management, when the more acute fractures at L3 showed complete bony union and the patient had symptomatic pain relief and was able to return to full sporting activity.

 Chang and colleagues² reported 10 patients with adjacent 2-level bilateral spondylolysis treated successfully using a pedicle screw–hook construct with autogenous bone grafting. Ogawa and colleagues⁵ reported adjacent 2-level spondylolysis in 5 patients and 3-level spondylolysis in 2 patients, who were treated successfully by segmental wire fixation and bone grafting. Ivanic and colleagues¹⁵ retrospectively reviewed 113 patients with spondylolysis who were treated with direct repair using a hook-screw construct and showed a pseudoarthrosis rate of 13.3%. Superior fusion rates were observed in patients 14 years and younger compared with older patients, particularly those 20 years and older.¹⁵ Roca and colleagues¹⁶ prospectively analyzed 19 consecutive cases of spondylolysis that were repaired using a hook-screw construct. Twelve of 13 patients (92%) who were 20 years or younger at the time of the study (average age, 17.2 years) had fusion, whereas, in 6 patients 21 years and older (average age, 27.5 years), no cases of fusion were observed. The patients 20 years or younger had significantly better clinical results than those obtained in the patients 21 years and older. The authors concluded that pedicle screw–hook fixation is a useful alternative in the treatment of spondylolysis in adolescents, but did not recommend this procedure in patients older than 20 years.¹⁶

Conclusion

The current case demonstrates a unique example of rare noncontiguous pars defects successfully treated with primary repair of 1 level when conservative management failed and the symptomatic defect was isolated. It also highlights the importance of investigating the entirety of the lumbar spine when diagnosis of L5 spondylolysis rules out noncontiguous pars defects. The treatment of noncontiguous pars defects is not well defined; this case showed the importance of using a SPECT scan and a diagnostic pars block to help isolate the symptomatic level when surgical management is considered after a failure of conservative treatment. This case shows 2 possible results: the chronic unilateral L5 defect responded to nonsurgical treatment with asymptomatic fibrous nonunion, while the more acute bilateral L2 defect responded to pars repair with pedicle screw–hook fixation and iliac crest bone graft. 

PHILADELPHIA – Women with epilepsy often reported having an increased number of seizures when taking a hormonal contraceptive, according to data collected from 1,144 women with epilepsy who completed an online survey.

The data showed that women who used hormonal contraception reported having an increased number of seizures while on the contraceptive about 4.5-fold more often than did women who used nonhormonal contraception. The risk for an increased number of seizures with hormonal contraception seemed greatest for women treated with valproate.

Until now, “valproate was generally accepted as okay to use” by women also taking a hormonal contraceptive, but the new findings suggest that if a woman of childbearing age with epilepsy needs valproate for seizure control she would be better off using a nonhormonal form of contraception such as an intrauterine device, Dr. Andrew G. Herzog said while presenting a poster at the annual meeting of the American Epilepsy Society.

Dr. Herzog highlighted the need for some form of contraception for most younger women on valproate because of the drug’s potential teratogenic effects, but he also stressed that the risk for increased seizures does not appear to affect a majority of women. The survey results showed that overall only 28% of women with epilepsy reported an increased seizure frequency when using a hormonal contraceptive.

“The first goal of a neurologist is to get seizures under control, and you go with the [antiepileptic drugs] that work,” Dr. Herzog said in an interview. Once an effective regimen is found, the physician can then deal with other issues, such as adverse effects as well as the potential for an adverse interaction with a hormonal contraceptive. Valproate can be the antiepileptic drug of choice as it is one of the most effective agents for controlling seizures in patients with primary generalized epilepsy, said Dr. Herzog, professor of neurology at Harvard Medical School, Boston, and director of the neuroendocrine unit of Beth Israel Deaconess Medical Center in Wellesley, Mass.

The new data come from an Internet-based survey, which is subject to biases and appeared to attract a preponderance of responses from women who were better educated and had higher incomes than did the general population. In addition, the researchers collected the data retrospectively. Despite these limitations, the results are notable because they represent the only data set yet reported from a community-based source large enough to allow analysis of the many clinical variables that play into the potential interactions between various contraceptive types, various antiepileptic drug classes, and the diverse number of epilepsy subtypes, he said. Dr. Herzog and his associates are planning a study to collect similar data prospectively, but the results would likely not be available for at least about 5 years, he noted.

The Epilepsy Birth Control Registry enrolled women with epilepsy aged 18-47 years who had a history of using at least one form of contraception while on antiepileptic treatment, and the 1,144 women who completed the survey reported a total of 2,712 contraceptive experiences. The survey asked women, “Do you think this method of birth control changed how often you had seizures?” with the option to reply that their contraceptive method seemed to increase, decrease, or not change their seizure number.

One of the analyses done by Dr. Herzog and his associates compared the responses by women on any form of hormonal contraceptive (combined or progestin pill, hormonal patch, vaginal ring, depot medroxyprogesterone acetate, or implanted hormone) with women on any form of nonhormonal contraception (withdrawal, male or female condom, copper or progestin intrauterine device, or tubal ligation).

The results showed that 72% of women on any hormonal contraceptive and 91% of women on any form of nonhormonal contraceptive reported no change in their seizure frequency. The rates of reporting an increased number of seizures were 19% with hormonal contraceptives and 4% with nonhormonal contraceptives, which computed to a relative risk of about 4.5-fold for an increased number of seizures while on hormonal contraception, compared with nonhormonal contraception, the researchers reported.

Barrier contraception (male or female condoms) had the lowest rate of seizure increase among any of the nonhormonal methods. The risk for greater seizure frequency on hormonal contraceptives of all types was 6.75-fold higher when compared specifically with barrier contraception.

In analyses of specific types of hormonal contraceptives, women using a hormonal patch reported a 68% greater incidence of seizure increases, compared with women using combined oral contraceptive pills (the hormonal method that produced the fewest episodes of seizure increases). Those using a progestin-only pill had a 62% higher rate of seizure increases.

More women on hormonal contraceptives also reported having a decrease in seizures after starting contraception, compared with those starting on a nonhormonal method (9.5% vs. 5.2%, respectively), which calculated to a 85% relative rate increase for decreased seizures. Depot medroxyprogesterone acetate was the only specific hormonal contraceptive that linked with a higher rate of seizure decreases, compared with combined oral pills, a 95% higher rate.

A second analysis of the results by Dr. Herzog and his associates examined the frequencies of seizure outcomes on hormonal and nonhormonal contraceptives stratifying by type of antiepileptic drug women used when starting a particular contraceptive method. This analysis broke down antiepileptic drugs into four types: enzyme inducing (29%), glucuronidated (such as lamotrigine; 27%), nonenzyme inducing (such as levetiracetam; 22%), enzyme inhibiting (valproate; 8%), and a fifth category that included women who were not on any antiepileptic drug (14%).

This analysis showed that the frequency of seizure increases was significantly greater with hormonal contraceptive use, compared with nonhormonal methods, across all five subgroups of antiepileptic drug type. In addition, the frequency of seizure increases with hormonal contraceptives differed significantly, depending on which antiepileptic drug type women used, but these significant differences among the antiepileptic drug types also occurred among women using nonhormonal contraception.

Women receiving a nonenzyme-inducing drug when starting a hormonal contraceptive reported the lowest frequency of seizure increases, a 12% rate. In contrast, women on an enzyme-inhibiting drug, valproate, had the highest rate of increased seizures when starting a hormonal contraceptive, 29%. This calculated out to about a 2.5-fold relative risk increase for having more seizures when starting hormonal contraception while on valproate, compared with women on a nonenzyme-inducing drug, Dr. Herzog reported.

Physicians “need to be on the lookout for the possibility that seizures could increase when women start a hormonal contraceptive,” he concluded.

[email protected]

On Twitter @mitchelzoler

PHILADELPHIA – Women with epilepsy often reported having an increased number of seizures when taking a hormonal contraceptive, according to data collected from 1,144 women with epilepsy who completed an online survey.

The data showed that women who used hormonal contraception reported having an increased number of seizures while on the contraceptive about 4.5-fold more often than did women who used nonhormonal contraception. The risk for an increased number of seizures with hormonal contraception seemed greatest for women treated with valproate.

Until now, “valproate was generally accepted as okay to use” by women also taking a hormonal contraceptive, but the new findings suggest that if a woman of childbearing age with epilepsy needs valproate for seizure control she would be better off using a nonhormonal form of contraception such as an intrauterine device, Dr. Andrew G. Herzog said while presenting a poster at the annual meeting of the American Epilepsy Society.

Dr. Herzog highlighted the need for some form of contraception for most younger women on valproate because of the drug’s potential teratogenic effects, but he also stressed that the risk for increased seizures does not appear to affect a majority of women. The survey results showed that overall only 28% of women with epilepsy reported an increased seizure frequency when using a hormonal contraceptive.

“The first goal of a neurologist is to get seizures under control, and you go with the [antiepileptic drugs] that work,” Dr. Herzog said in an interview. Once an effective regimen is found, the physician can then deal with other issues, such as adverse effects as well as the potential for an adverse interaction with a hormonal contraceptive. Valproate can be the antiepileptic drug of choice as it is one of the most effective agents for controlling seizures in patients with primary generalized epilepsy, said Dr. Herzog, professor of neurology at Harvard Medical School, Boston, and director of the neuroendocrine unit of Beth Israel Deaconess Medical Center in Wellesley, Mass.

The new data come from an Internet-based survey, which is subject to biases and appeared to attract a preponderance of responses from women who were better educated and had higher incomes than did the general population. In addition, the researchers collected the data retrospectively. Despite these limitations, the results are notable because they represent the only data set yet reported from a community-based source large enough to allow analysis of the many clinical variables that play into the potential interactions between various contraceptive types, various antiepileptic drug classes, and the diverse number of epilepsy subtypes, he said. Dr. Herzog and his associates are planning a study to collect similar data prospectively, but the results would likely not be available for at least about 5 years, he noted.

The Epilepsy Birth Control Registry enrolled women with epilepsy aged 18-47 years who had a history of using at least one form of contraception while on antiepileptic treatment, and the 1,144 women who completed the survey reported a total of 2,712 contraceptive experiences. The survey asked women, “Do you think this method of birth control changed how often you had seizures?” with the option to reply that their contraceptive method seemed to increase, decrease, or not change their seizure number.

One of the analyses done by Dr. Herzog and his associates compared the responses by women on any form of hormonal contraceptive (combined or progestin pill, hormonal patch, vaginal ring, depot medroxyprogesterone acetate, or implanted hormone) with women on any form of nonhormonal contraception (withdrawal, male or female condom, copper or progestin intrauterine device, or tubal ligation).

The results showed that 72% of women on any hormonal contraceptive and 91% of women on any form of nonhormonal contraceptive reported no change in their seizure frequency. The rates of reporting an increased number of seizures were 19% with hormonal contraceptives and 4% with nonhormonal contraceptives, which computed to a relative risk of about 4.5-fold for an increased number of seizures while on hormonal contraception, compared with nonhormonal contraception, the researchers reported.

Barrier contraception (male or female condoms) had the lowest rate of seizure increase among any of the nonhormonal methods. The risk for greater seizure frequency on hormonal contraceptives of all types was 6.75-fold higher when compared specifically with barrier contraception.

In analyses of specific types of hormonal contraceptives, women using a hormonal patch reported a 68% greater incidence of seizure increases, compared with women using combined oral contraceptive pills (the hormonal method that produced the fewest episodes of seizure increases). Those using a progestin-only pill had a 62% higher rate of seizure increases.

More women on hormonal contraceptives also reported having a decrease in seizures after starting contraception, compared with those starting on a nonhormonal method (9.5% vs. 5.2%, respectively), which calculated to a 85% relative rate increase for decreased seizures. Depot medroxyprogesterone acetate was the only specific hormonal contraceptive that linked with a higher rate of seizure decreases, compared with combined oral pills, a 95% higher rate.

A second analysis of the results by Dr. Herzog and his associates examined the frequencies of seizure outcomes on hormonal and nonhormonal contraceptives stratifying by type of antiepileptic drug women used when starting a particular contraceptive method. This analysis broke down antiepileptic drugs into four types: enzyme inducing (29%), glucuronidated (such as lamotrigine; 27%), nonenzyme inducing (such as levetiracetam; 22%), enzyme inhibiting (valproate; 8%), and a fifth category that included women who were not on any antiepileptic drug (14%).

This analysis showed that the frequency of seizure increases was significantly greater with hormonal contraceptive use, compared with nonhormonal methods, across all five subgroups of antiepileptic drug type. In addition, the frequency of seizure increases with hormonal contraceptives differed significantly, depending on which antiepileptic drug type women used, but these significant differences among the antiepileptic drug types also occurred among women using nonhormonal contraception.

Women receiving a nonenzyme-inducing drug when starting a hormonal contraceptive reported the lowest frequency of seizure increases, a 12% rate. In contrast, women on an enzyme-inhibiting drug, valproate, had the highest rate of increased seizures when starting a hormonal contraceptive, 29%. This calculated out to about a 2.5-fold relative risk increase for having more seizures when starting hormonal contraception while on valproate, compared with women on a nonenzyme-inducing drug, Dr. Herzog reported.

Physicians “need to be on the lookout for the possibility that seizures could increase when women start a hormonal contraceptive,” he concluded.

[email protected]

On Twitter @mitchelzoler

PHILADELPHIA – Women with epilepsy often reported having an increased number of seizures when taking a hormonal contraceptive, according to data collected from 1,144 women with epilepsy who completed an online survey.

The data showed that women who used hormonal contraception reported having an increased number of seizures while on the contraceptive about 4.5-fold more often than did women who used nonhormonal contraception. The risk for an increased number of seizures with hormonal contraception seemed greatest for women treated with valproate.

Until now, “valproate was generally accepted as okay to use” by women also taking a hormonal contraceptive, but the new findings suggest that if a woman of childbearing age with epilepsy needs valproate for seizure control she would be better off using a nonhormonal form of contraception such as an intrauterine device, Dr. Andrew G. Herzog said while presenting a poster at the annual meeting of the American Epilepsy Society.

Dr. Herzog highlighted the need for some form of contraception for most younger women on valproate because of the drug’s potential teratogenic effects, but he also stressed that the risk for increased seizures does not appear to affect a majority of women. The survey results showed that overall only 28% of women with epilepsy reported an increased seizure frequency when using a hormonal contraceptive.

“The first goal of a neurologist is to get seizures under control, and you go with the [antiepileptic drugs] that work,” Dr. Herzog said in an interview. Once an effective regimen is found, the physician can then deal with other issues, such as adverse effects as well as the potential for an adverse interaction with a hormonal contraceptive. Valproate can be the antiepileptic drug of choice as it is one of the most effective agents for controlling seizures in patients with primary generalized epilepsy, said Dr. Herzog, professor of neurology at Harvard Medical School, Boston, and director of the neuroendocrine unit of Beth Israel Deaconess Medical Center in Wellesley, Mass.

The new data come from an Internet-based survey, which is subject to biases and appeared to attract a preponderance of responses from women who were better educated and had higher incomes than did the general population. In addition, the researchers collected the data retrospectively. Despite these limitations, the results are notable because they represent the only data set yet reported from a community-based source large enough to allow analysis of the many clinical variables that play into the potential interactions between various contraceptive types, various antiepileptic drug classes, and the diverse number of epilepsy subtypes, he said. Dr. Herzog and his associates are planning a study to collect similar data prospectively, but the results would likely not be available for at least about 5 years, he noted.

The Epilepsy Birth Control Registry enrolled women with epilepsy aged 18-47 years who had a history of using at least one form of contraception while on antiepileptic treatment, and the 1,144 women who completed the survey reported a total of 2,712 contraceptive experiences. The survey asked women, “Do you think this method of birth control changed how often you had seizures?” with the option to reply that their contraceptive method seemed to increase, decrease, or not change their seizure number.

One of the analyses done by Dr. Herzog and his associates compared the responses by women on any form of hormonal contraceptive (combined or progestin pill, hormonal patch, vaginal ring, depot medroxyprogesterone acetate, or implanted hormone) with women on any form of nonhormonal contraception (withdrawal, male or female condom, copper or progestin intrauterine device, or tubal ligation).

The results showed that 72% of women on any hormonal contraceptive and 91% of women on any form of nonhormonal contraceptive reported no change in their seizure frequency. The rates of reporting an increased number of seizures were 19% with hormonal contraceptives and 4% with nonhormonal contraceptives, which computed to a relative risk of about 4.5-fold for an increased number of seizures while on hormonal contraception, compared with nonhormonal contraception, the researchers reported.

Barrier contraception (male or female condoms) had the lowest rate of seizure increase among any of the nonhormonal methods. The risk for greater seizure frequency on hormonal contraceptives of all types was 6.75-fold higher when compared specifically with barrier contraception.

In analyses of specific types of hormonal contraceptives, women using a hormonal patch reported a 68% greater incidence of seizure increases, compared with women using combined oral contraceptive pills (the hormonal method that produced the fewest episodes of seizure increases). Those using a progestin-only pill had a 62% higher rate of seizure increases.

More women on hormonal contraceptives also reported having a decrease in seizures after starting contraception, compared with those starting on a nonhormonal method (9.5% vs. 5.2%, respectively), which calculated to a 85% relative rate increase for decreased seizures. Depot medroxyprogesterone acetate was the only specific hormonal contraceptive that linked with a higher rate of seizure decreases, compared with combined oral pills, a 95% higher rate.

A second analysis of the results by Dr. Herzog and his associates examined the frequencies of seizure outcomes on hormonal and nonhormonal contraceptives stratifying by type of antiepileptic drug women used when starting a particular contraceptive method. This analysis broke down antiepileptic drugs into four types: enzyme inducing (29%), glucuronidated (such as lamotrigine; 27%), nonenzyme inducing (such as levetiracetam; 22%), enzyme inhibiting (valproate; 8%), and a fifth category that included women who were not on any antiepileptic drug (14%).

This analysis showed that the frequency of seizure increases was significantly greater with hormonal contraceptive use, compared with nonhormonal methods, across all five subgroups of antiepileptic drug type. In addition, the frequency of seizure increases with hormonal contraceptives differed significantly, depending on which antiepileptic drug type women used, but these significant differences among the antiepileptic drug types also occurred among women using nonhormonal contraception.

Women receiving a nonenzyme-inducing drug when starting a hormonal contraceptive reported the lowest frequency of seizure increases, a 12% rate. In contrast, women on an enzyme-inhibiting drug, valproate, had the highest rate of increased seizures when starting a hormonal contraceptive, 29%. This calculated out to about a 2.5-fold relative risk increase for having more seizures when starting hormonal contraception while on valproate, compared with women on a nonenzyme-inducing drug, Dr. Herzog reported.

Physicians “need to be on the lookout for the possibility that seizures could increase when women start a hormonal contraceptive,” he concluded.

[email protected]

On Twitter @mitchelzoler

Vancomycin is a glycopeptide antibiotic that exhibits bactericidal activity against gram-positive cocci. It is commonly recommended for surgical prophylaxis in cases of suspected bacterial resistance or penicillin allergy.¹ Two main types of hypersensitivity reactions associated with vancomycin can have similar presentations. Red man syndrome is an anaphylactoid reaction caused by direct release of histamine from mast cells via a nonimmunologic mechanism, and is the more common of the 2 reactions. The second type is an anaphylactic reaction, which is an immunoglobulin E (IgE)–mediated systemic event and requires exposure to become sensitized.^2,3

We present a patient who had received vancomycin on at least 12 occasions without incident. On this occasion, however, she developed a true anaphylactic reaction causing acute hemodynamic collapse that she survived after extensive resuscitation. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 55-year-old woman had a history of metastatic giant cell tumor of the right proximal tibia. She was originally treated 27 years ago for proximal tibial resection and reconstruction with a custom proximal tibial prosthesis. Four months later, she underwent resection of multiple pulmonary metastases via bilateral thoracotomies in a single surgical setting. After this, the patient had no evidence of recurrent metastatic disease. In subsequent years, the patient underwent multiple revision surgeries for problems such as hardware failure, patellar maltracking, and infection. The patient underwent 19 operations, including several nonorthopedic procedures. Because the patient had a rash after receiving penicillin as a child, she was thought to be allergic to penicillin. Consequently, she received vancomycin as antibiotic prophylaxis for the majority of these procedures. She also received extended courses of vancomycin of at least 6 weeks on 2 separate occasions. During her most recent revision procedure, 6 weeks prior to the procedure under discussion, the patient took vancomycin without incident. She was then found to have a prosthetic infection with Staphylococcus epidermidis, the same organism isolated in her previous infections, and she was advised to undergo a staged revision.

After a preoperative medical evaluation by her primary care physician, the patient was taken to the operating room for prosthesis removal and antibiotic spacer placement. She was anemic with a hemoglobin level of 8.8 g/dL; her erythrocyte sedimentation rate (ESR) was 102 mm/h (normal, <22 mm/h) and her C-reactive protein (CRP) was 38 mg/L (normal, <3 mg/L), but, otherwise, her laboratory values were normal, including a white blood cell count (WBC) of 8100/µL. Her electrocardiogram showed a normal sinus rhythm with nonspecific ST- and T-wave changes. Antibiotics were held until after cultures were taken. General endotracheal tube anesthesia was induced with 2 mg midazolam, 100 µg fentanyl, 180 mg propofol, and 140 mg succinylcholine, followed by 10 mg vecuronium, and maintained with desflurane. A tourniquet was not used per the surgeon’s routine. Dissection was carried down to the prosthesis and showed a small amount of purulent fluid. Transfusion of 1 unit of packed red blood cells (pRBC) was started during the approach owing to relatively low preoperative hemoglobin and significant blood loss. Approximately 500 mL of blood was lost during the approach secondary to the extensive dissection and the local inflammatory response from infection and recent surgery. After cultures were taken, and approximately 10 minutes after blood transfusion began, infusion of 1 g vancomycin in 250 mL normal saline was started via an infusion pump to run over 1 hour.

After infusion of 5 mL vancomycin, the patient’s blood pressure dropped from 117/63 mm Hg to 63/30 mm Hg; her pulse concurrently dropped from 90 to 50 beats/min. Vancomycin infusion was immediately stopped, anesthesia gasses were turned off, and patient received a bolus of normal saline with a second unit of pRBC. Patient received boluses of 0.5 mg to 1.0 mg epinephrine and 100 µg phenylephrine without sustained increase in blood pressure, which had dropped to 54/24 mm Hg, although the patient became tachycardic to ~120 beats/min after epinephrine. A sudden drop in end-tidal CO₂ from 40s mm Hg to 20s mm Hg was also noted, indicating continuous but significantly decreased perfusion of the lungs.

We elected to abort the procedure, and a vacuum-assisted closure (VAC) dressing was applied to the open wound. After 15 minutes, the patient’s pulses, which had been faint, became impalpable, and cardiopulmonary resuscitation was initiated for about 7 minutes. The patient received 40 units vasopressin with repeated boluses of 0.5 mg epinephrine; a norepinephrine continuous infusion was started with the return of pulses. The patient also received 50 mg diphenhydramine, 125 mg methylprednisolone, and 20 mg famotidine for suspected anaphylaxis. A central venous line and arterial line were placed, and blood was drawn for laboratory analysis. The patient was noted to have clear breath sounds with no obvious rash, and her urine remained clear. Blood gas showed a profound metabolic acidosis, with pH of 7.09, base deficit of 5.9, and lactate of 8.9. The patient was treated with bicarbonate infusion. The patient was noted to ooze significantly during central venous line and arterial line placement, despite apparently normal coagulation during the surgical approach. Coagulation values were consistent with disseminated intravascular coagulation (DIC): prothrombin time, 57 s (international normalized ratio, 6.7); partial thromboplastin time, >200 s; thrombin time, 110 s; D-dimer, >10,000 ng/mL (normal, 0-200 ng/mL); and fibrinogen, <60 mg/dL (normal, 222-475 mg/dL). The patient’s thromboelastogram showed a flat line indicating an absence of clotting. Interestingly, the platelet count remained near the preoperative level at 338×10³/µL. The patient’s blood pressure remained labile and was responsive primarily to epinephrine boluses, of which she received a total of 5 mg. After 1 hour of resuscitation, during which time the patient received a total of 5 L crystalloid and 3 units pRBC, the patient was transferred to the intensive care unit (ICU), intubated, and started on a titrated epinephrine infusion.

Upon arrival in the ICU, the patient quickly stabilized hemodynamically. She was weaned from all inotropic support within 2 hours of arrival. The patient lost 800 mL of blood through wound VAC over the first 12 hours postoperatively and required a total of 11 units of pRBC, 6 units fresh frozen plasma, and 3 units of pooled cryoprecipitate, all of which were compatible. Laboratory values, including arterial pH, lactic acid, and coagulation studies, normalized on the evening of surgery, and, by the next morning, the patient was alert and was extubated without difficulty. Steroids were tapered without hemodynamic compromise while the patient was in the ICU. Cardiology examination revealed no abnormalities. Because of the temporal association of blood transfusion with cardiovascular collapse, pRBC units were retested for antibodies and cultured. Both of these investigations were negative. Wound cultures again were positive for Staphylococcus epidermidis, and blood cultures were negative. The patient was started on daptomycin based on susceptibility profiles. Serum histamine levels taken during initial resuscitation in the operating room were normal. The serum tryptase level obtained at the same time was markedly elevated at >700 ng/mL (normal, <11.5 ng/mL), although this information was not available until several days later.

The patient underwent 2 additional surgeries during the same admission, including the prosthesis removal and tobramycin cement spacer placement, without incident. She was discharged home, again without incident. The patient was later evaluated by an outside allergist and underwent skin puncture and intradermal allergy testing. The results were consistent with a strong IgE-mediated hypersensitivity. Interestingly, she was found not to have a penicillin allergy.

Discussion

Vancomycin hypersensitivity reactions include the anaphylactoid reaction red man syndrome and a true IgE-mediated anaphylactic reaction. Red man syndrome is much more common, with reported rates in infected patients from 3.7% to 47%,^4,5 when vancomycin is given at the suggested  rate of 1 g over 1 hour. The reaction occurs because of histamine release from mast cells and basophils, and does not require previous sensitization.³ The rate of infusion is directly related to the development of symptoms, with 100% of patients developing symptoms in 1 study with rapid infusion (1 g over 10 min).⁶ Red man syndrome can typically be prevented by slowing the rate of infusion or by giving an H₁ blocker.³ Anaphylaxis is more rare but can occur.⁷ Anaphylaxis is mediated by vancomycin-specific IgE, which requires previous exposure, as was the case with our patient. Interestingly, the patient had received vancomycin many times without any signs of a hypersensitivity reaction. Antihistamines are not effective in treating anaphylaxis, and epinephrine is the first-line agent.³ This was clearly demonstrated in this case, as there was a significant hemodynamic response to epinephrine and a negligible response to other vasopressors, specifically norepinephrine and vasopressin.

Most hypersensitivity reactions during the course of a surgical procedure occur with induction of anesthesia, with neuromuscular blocking agents and antibiotics being the most common causes.⁸ In our case, antibiotics were held until after deep cultures were taken. Given the time from induction to the anaphylactic reaction, it is unlikely the reaction resulted from the induction agents or the neuromuscular blocking agent. The possibility of a transfusion reaction was also investigated, since a unit of pRBC was still being transfused when symptoms began. An acute hemolytic transfusion reaction has the classic triad of fever, flank pain, and hemoglobinuria, and can also present as DIC.⁹ Under anesthesia, DIC can often be the presenting sign. In this case, a hemolytic transfusion reaction appeared very unlikely. All of the blood components the patient received were rechecked and found to be compatible, posttransfusion analysis showed no evidence of hemolysis in any sample, and the direct antiglobulin test was negative in all components.

To our knowledge, there are no reported cases of vancomycin-induced anaphylaxis with concomitant DIC. Symptoms of anaphylaxis after exposure to a possible antigen include rapid onset of hypotension or rapid onset of signs in at least 2 organ systems, including cutaneous, gastrointestinal, respiratory, and cardiovascular.¹⁰ Anaphylaxis with DIC is rare after exposure to any substance but has been reported.¹¹ In fact, induction of systemic anaphylaxis in mice is known to cause DIC, with platelet-activating factor suggested as an important common mediator. A similar mechanism is suspected in humans.¹²

Confirmation of, and, certainly, prediction of, a vancomycin hypersensitivity reaction is difficult. Histamine levels can be used as a measure of mast-cell degranulation, but serum levels peak within 5 minutes and quickly return to baseline, limiting its diagnostic usefulness.³ Tryptase is an enzyme found in the secretory granules of mast cells. It has become an accepted marker of acute anaphylaxis, and, in vancomycin hypersensitivity reactions, can also distinguish between anaphylactic and anaphylactoid reactions.¹³ Tryptase levels peak 1 to 2 hours after the reaction, making this easier to measure than histamine, but results may not be available for several days, making it useful only in retrospect, as in our case. Skin testing is probably the best way to confirm a hypersensitivity reaction, although even this has been questioned with vancomycin because some find a high false-positive rate³, while others think the false-negative rate is likely too high.⁷ In this case, we were able to confirm our initial clinical suspicion with both an elevated tryptase level and a positive skin test.

Conclusion

We present a rare case of vancomycin anaphylaxis with DIC after repeated and prolonged previous exposure, which was treated acutely with hemodynamic resuscitation, replacement of blood components, steroids, and, most importantly, repeated boluses of epinephrine. Although several papers have described successful vancomycin desensitization⁷, this was fortunately not necessary in this case because the causative organism was sensitive to other acceptable antibiotics. The patient has been treated with systemic daptomycin and a tobramycin cement spacer without further incident.

Vancomycin is a glycopeptide antibiotic that exhibits bactericidal activity against gram-positive cocci. It is commonly recommended for surgical prophylaxis in cases of suspected bacterial resistance or penicillin allergy.¹ Two main types of hypersensitivity reactions associated with vancomycin can have similar presentations. Red man syndrome is an anaphylactoid reaction caused by direct release of histamine from mast cells via a nonimmunologic mechanism, and is the more common of the 2 reactions. The second type is an anaphylactic reaction, which is an immunoglobulin E (IgE)–mediated systemic event and requires exposure to become sensitized.^2,3

We present a patient who had received vancomycin on at least 12 occasions without incident. On this occasion, however, she developed a true anaphylactic reaction causing acute hemodynamic collapse that she survived after extensive resuscitation. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 55-year-old woman had a history of metastatic giant cell tumor of the right proximal tibia. She was originally treated 27 years ago for proximal tibial resection and reconstruction with a custom proximal tibial prosthesis. Four months later, she underwent resection of multiple pulmonary metastases via bilateral thoracotomies in a single surgical setting. After this, the patient had no evidence of recurrent metastatic disease. In subsequent years, the patient underwent multiple revision surgeries for problems such as hardware failure, patellar maltracking, and infection. The patient underwent 19 operations, including several nonorthopedic procedures. Because the patient had a rash after receiving penicillin as a child, she was thought to be allergic to penicillin. Consequently, she received vancomycin as antibiotic prophylaxis for the majority of these procedures. She also received extended courses of vancomycin of at least 6 weeks on 2 separate occasions. During her most recent revision procedure, 6 weeks prior to the procedure under discussion, the patient took vancomycin without incident. She was then found to have a prosthetic infection with Staphylococcus epidermidis, the same organism isolated in her previous infections, and she was advised to undergo a staged revision.

After a preoperative medical evaluation by her primary care physician, the patient was taken to the operating room for prosthesis removal and antibiotic spacer placement. She was anemic with a hemoglobin level of 8.8 g/dL; her erythrocyte sedimentation rate (ESR) was 102 mm/h (normal, <22 mm/h) and her C-reactive protein (CRP) was 38 mg/L (normal, <3 mg/L), but, otherwise, her laboratory values were normal, including a white blood cell count (WBC) of 8100/µL. Her electrocardiogram showed a normal sinus rhythm with nonspecific ST- and T-wave changes. Antibiotics were held until after cultures were taken. General endotracheal tube anesthesia was induced with 2 mg midazolam, 100 µg fentanyl, 180 mg propofol, and 140 mg succinylcholine, followed by 10 mg vecuronium, and maintained with desflurane. A tourniquet was not used per the surgeon’s routine. Dissection was carried down to the prosthesis and showed a small amount of purulent fluid. Transfusion of 1 unit of packed red blood cells (pRBC) was started during the approach owing to relatively low preoperative hemoglobin and significant blood loss. Approximately 500 mL of blood was lost during the approach secondary to the extensive dissection and the local inflammatory response from infection and recent surgery. After cultures were taken, and approximately 10 minutes after blood transfusion began, infusion of 1 g vancomycin in 250 mL normal saline was started via an infusion pump to run over 1 hour.

After infusion of 5 mL vancomycin, the patient’s blood pressure dropped from 117/63 mm Hg to 63/30 mm Hg; her pulse concurrently dropped from 90 to 50 beats/min. Vancomycin infusion was immediately stopped, anesthesia gasses were turned off, and patient received a bolus of normal saline with a second unit of pRBC. Patient received boluses of 0.5 mg to 1.0 mg epinephrine and 100 µg phenylephrine without sustained increase in blood pressure, which had dropped to 54/24 mm Hg, although the patient became tachycardic to ~120 beats/min after epinephrine. A sudden drop in end-tidal CO₂ from 40s mm Hg to 20s mm Hg was also noted, indicating continuous but significantly decreased perfusion of the lungs.

We elected to abort the procedure, and a vacuum-assisted closure (VAC) dressing was applied to the open wound. After 15 minutes, the patient’s pulses, which had been faint, became impalpable, and cardiopulmonary resuscitation was initiated for about 7 minutes. The patient received 40 units vasopressin with repeated boluses of 0.5 mg epinephrine; a norepinephrine continuous infusion was started with the return of pulses. The patient also received 50 mg diphenhydramine, 125 mg methylprednisolone, and 20 mg famotidine for suspected anaphylaxis. A central venous line and arterial line were placed, and blood was drawn for laboratory analysis. The patient was noted to have clear breath sounds with no obvious rash, and her urine remained clear. Blood gas showed a profound metabolic acidosis, with pH of 7.09, base deficit of 5.9, and lactate of 8.9. The patient was treated with bicarbonate infusion. The patient was noted to ooze significantly during central venous line and arterial line placement, despite apparently normal coagulation during the surgical approach. Coagulation values were consistent with disseminated intravascular coagulation (DIC): prothrombin time, 57 s (international normalized ratio, 6.7); partial thromboplastin time, >200 s; thrombin time, 110 s; D-dimer, >10,000 ng/mL (normal, 0-200 ng/mL); and fibrinogen, <60 mg/dL (normal, 222-475 mg/dL). The patient’s thromboelastogram showed a flat line indicating an absence of clotting. Interestingly, the platelet count remained near the preoperative level at 338×10³/µL. The patient’s blood pressure remained labile and was responsive primarily to epinephrine boluses, of which she received a total of 5 mg. After 1 hour of resuscitation, during which time the patient received a total of 5 L crystalloid and 3 units pRBC, the patient was transferred to the intensive care unit (ICU), intubated, and started on a titrated epinephrine infusion.

Upon arrival in the ICU, the patient quickly stabilized hemodynamically. She was weaned from all inotropic support within 2 hours of arrival. The patient lost 800 mL of blood through wound VAC over the first 12 hours postoperatively and required a total of 11 units of pRBC, 6 units fresh frozen plasma, and 3 units of pooled cryoprecipitate, all of which were compatible. Laboratory values, including arterial pH, lactic acid, and coagulation studies, normalized on the evening of surgery, and, by the next morning, the patient was alert and was extubated without difficulty. Steroids were tapered without hemodynamic compromise while the patient was in the ICU. Cardiology examination revealed no abnormalities. Because of the temporal association of blood transfusion with cardiovascular collapse, pRBC units were retested for antibodies and cultured. Both of these investigations were negative. Wound cultures again were positive for Staphylococcus epidermidis, and blood cultures were negative. The patient was started on daptomycin based on susceptibility profiles. Serum histamine levels taken during initial resuscitation in the operating room were normal. The serum tryptase level obtained at the same time was markedly elevated at >700 ng/mL (normal, <11.5 ng/mL), although this information was not available until several days later.

The patient underwent 2 additional surgeries during the same admission, including the prosthesis removal and tobramycin cement spacer placement, without incident. She was discharged home, again without incident. The patient was later evaluated by an outside allergist and underwent skin puncture and intradermal allergy testing. The results were consistent with a strong IgE-mediated hypersensitivity. Interestingly, she was found not to have a penicillin allergy.

Discussion

Vancomycin hypersensitivity reactions include the anaphylactoid reaction red man syndrome and a true IgE-mediated anaphylactic reaction. Red man syndrome is much more common, with reported rates in infected patients from 3.7% to 47%,^4,5 when vancomycin is given at the suggested  rate of 1 g over 1 hour. The reaction occurs because of histamine release from mast cells and basophils, and does not require previous sensitization.³ The rate of infusion is directly related to the development of symptoms, with 100% of patients developing symptoms in 1 study with rapid infusion (1 g over 10 min).⁶ Red man syndrome can typically be prevented by slowing the rate of infusion or by giving an H₁ blocker.³ Anaphylaxis is more rare but can occur.⁷ Anaphylaxis is mediated by vancomycin-specific IgE, which requires previous exposure, as was the case with our patient. Interestingly, the patient had received vancomycin many times without any signs of a hypersensitivity reaction. Antihistamines are not effective in treating anaphylaxis, and epinephrine is the first-line agent.³ This was clearly demonstrated in this case, as there was a significant hemodynamic response to epinephrine and a negligible response to other vasopressors, specifically norepinephrine and vasopressin.

Most hypersensitivity reactions during the course of a surgical procedure occur with induction of anesthesia, with neuromuscular blocking agents and antibiotics being the most common causes.⁸ In our case, antibiotics were held until after deep cultures were taken. Given the time from induction to the anaphylactic reaction, it is unlikely the reaction resulted from the induction agents or the neuromuscular blocking agent. The possibility of a transfusion reaction was also investigated, since a unit of pRBC was still being transfused when symptoms began. An acute hemolytic transfusion reaction has the classic triad of fever, flank pain, and hemoglobinuria, and can also present as DIC.⁹ Under anesthesia, DIC can often be the presenting sign. In this case, a hemolytic transfusion reaction appeared very unlikely. All of the blood components the patient received were rechecked and found to be compatible, posttransfusion analysis showed no evidence of hemolysis in any sample, and the direct antiglobulin test was negative in all components.

To our knowledge, there are no reported cases of vancomycin-induced anaphylaxis with concomitant DIC. Symptoms of anaphylaxis after exposure to a possible antigen include rapid onset of hypotension or rapid onset of signs in at least 2 organ systems, including cutaneous, gastrointestinal, respiratory, and cardiovascular.¹⁰ Anaphylaxis with DIC is rare after exposure to any substance but has been reported.¹¹ In fact, induction of systemic anaphylaxis in mice is known to cause DIC, with platelet-activating factor suggested as an important common mediator. A similar mechanism is suspected in humans.¹²

Confirmation of, and, certainly, prediction of, a vancomycin hypersensitivity reaction is difficult. Histamine levels can be used as a measure of mast-cell degranulation, but serum levels peak within 5 minutes and quickly return to baseline, limiting its diagnostic usefulness.³ Tryptase is an enzyme found in the secretory granules of mast cells. It has become an accepted marker of acute anaphylaxis, and, in vancomycin hypersensitivity reactions, can also distinguish between anaphylactic and anaphylactoid reactions.¹³ Tryptase levels peak 1 to 2 hours after the reaction, making this easier to measure than histamine, but results may not be available for several days, making it useful only in retrospect, as in our case. Skin testing is probably the best way to confirm a hypersensitivity reaction, although even this has been questioned with vancomycin because some find a high false-positive rate³, while others think the false-negative rate is likely too high.⁷ In this case, we were able to confirm our initial clinical suspicion with both an elevated tryptase level and a positive skin test.

Conclusion

We present a rare case of vancomycin anaphylaxis with DIC after repeated and prolonged previous exposure, which was treated acutely with hemodynamic resuscitation, replacement of blood components, steroids, and, most importantly, repeated boluses of epinephrine. Although several papers have described successful vancomycin desensitization⁷, this was fortunately not necessary in this case because the causative organism was sensitive to other acceptable antibiotics. The patient has been treated with systemic daptomycin and a tobramycin cement spacer without further incident.

Vancomycin is a glycopeptide antibiotic that exhibits bactericidal activity against gram-positive cocci. It is commonly recommended for surgical prophylaxis in cases of suspected bacterial resistance or penicillin allergy.¹ Two main types of hypersensitivity reactions associated with vancomycin can have similar presentations. Red man syndrome is an anaphylactoid reaction caused by direct release of histamine from mast cells via a nonimmunologic mechanism, and is the more common of the 2 reactions. The second type is an anaphylactic reaction, which is an immunoglobulin E (IgE)–mediated systemic event and requires exposure to become sensitized.^2,3

We present a patient who had received vancomycin on at least 12 occasions without incident. On this occasion, however, she developed a true anaphylactic reaction causing acute hemodynamic collapse that she survived after extensive resuscitation. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 55-year-old woman had a history of metastatic giant cell tumor of the right proximal tibia. She was originally treated 27 years ago for proximal tibial resection and reconstruction with a custom proximal tibial prosthesis. Four months later, she underwent resection of multiple pulmonary metastases via bilateral thoracotomies in a single surgical setting. After this, the patient had no evidence of recurrent metastatic disease. In subsequent years, the patient underwent multiple revision surgeries for problems such as hardware failure, patellar maltracking, and infection. The patient underwent 19 operations, including several nonorthopedic procedures. Because the patient had a rash after receiving penicillin as a child, she was thought to be allergic to penicillin. Consequently, she received vancomycin as antibiotic prophylaxis for the majority of these procedures. She also received extended courses of vancomycin of at least 6 weeks on 2 separate occasions. During her most recent revision procedure, 6 weeks prior to the procedure under discussion, the patient took vancomycin without incident. She was then found to have a prosthetic infection with Staphylococcus epidermidis, the same organism isolated in her previous infections, and she was advised to undergo a staged revision.

After a preoperative medical evaluation by her primary care physician, the patient was taken to the operating room for prosthesis removal and antibiotic spacer placement. She was anemic with a hemoglobin level of 8.8 g/dL; her erythrocyte sedimentation rate (ESR) was 102 mm/h (normal, <22 mm/h) and her C-reactive protein (CRP) was 38 mg/L (normal, <3 mg/L), but, otherwise, her laboratory values were normal, including a white blood cell count (WBC) of 8100/µL. Her electrocardiogram showed a normal sinus rhythm with nonspecific ST- and T-wave changes. Antibiotics were held until after cultures were taken. General endotracheal tube anesthesia was induced with 2 mg midazolam, 100 µg fentanyl, 180 mg propofol, and 140 mg succinylcholine, followed by 10 mg vecuronium, and maintained with desflurane. A tourniquet was not used per the surgeon’s routine. Dissection was carried down to the prosthesis and showed a small amount of purulent fluid. Transfusion of 1 unit of packed red blood cells (pRBC) was started during the approach owing to relatively low preoperative hemoglobin and significant blood loss. Approximately 500 mL of blood was lost during the approach secondary to the extensive dissection and the local inflammatory response from infection and recent surgery. After cultures were taken, and approximately 10 minutes after blood transfusion began, infusion of 1 g vancomycin in 250 mL normal saline was started via an infusion pump to run over 1 hour.

After infusion of 5 mL vancomycin, the patient’s blood pressure dropped from 117/63 mm Hg to 63/30 mm Hg; her pulse concurrently dropped from 90 to 50 beats/min. Vancomycin infusion was immediately stopped, anesthesia gasses were turned off, and patient received a bolus of normal saline with a second unit of pRBC. Patient received boluses of 0.5 mg to 1.0 mg epinephrine and 100 µg phenylephrine without sustained increase in blood pressure, which had dropped to 54/24 mm Hg, although the patient became tachycardic to ~120 beats/min after epinephrine. A sudden drop in end-tidal CO₂ from 40s mm Hg to 20s mm Hg was also noted, indicating continuous but significantly decreased perfusion of the lungs.

We elected to abort the procedure, and a vacuum-assisted closure (VAC) dressing was applied to the open wound. After 15 minutes, the patient’s pulses, which had been faint, became impalpable, and cardiopulmonary resuscitation was initiated for about 7 minutes. The patient received 40 units vasopressin with repeated boluses of 0.5 mg epinephrine; a norepinephrine continuous infusion was started with the return of pulses. The patient also received 50 mg diphenhydramine, 125 mg methylprednisolone, and 20 mg famotidine for suspected anaphylaxis. A central venous line and arterial line were placed, and blood was drawn for laboratory analysis. The patient was noted to have clear breath sounds with no obvious rash, and her urine remained clear. Blood gas showed a profound metabolic acidosis, with pH of 7.09, base deficit of 5.9, and lactate of 8.9. The patient was treated with bicarbonate infusion. The patient was noted to ooze significantly during central venous line and arterial line placement, despite apparently normal coagulation during the surgical approach. Coagulation values were consistent with disseminated intravascular coagulation (DIC): prothrombin time, 57 s (international normalized ratio, 6.7); partial thromboplastin time, >200 s; thrombin time, 110 s; D-dimer, >10,000 ng/mL (normal, 0-200 ng/mL); and fibrinogen, <60 mg/dL (normal, 222-475 mg/dL). The patient’s thromboelastogram showed a flat line indicating an absence of clotting. Interestingly, the platelet count remained near the preoperative level at 338×10³/µL. The patient’s blood pressure remained labile and was responsive primarily to epinephrine boluses, of which she received a total of 5 mg. After 1 hour of resuscitation, during which time the patient received a total of 5 L crystalloid and 3 units pRBC, the patient was transferred to the intensive care unit (ICU), intubated, and started on a titrated epinephrine infusion.

Upon arrival in the ICU, the patient quickly stabilized hemodynamically. She was weaned from all inotropic support within 2 hours of arrival. The patient lost 800 mL of blood through wound VAC over the first 12 hours postoperatively and required a total of 11 units of pRBC, 6 units fresh frozen plasma, and 3 units of pooled cryoprecipitate, all of which were compatible. Laboratory values, including arterial pH, lactic acid, and coagulation studies, normalized on the evening of surgery, and, by the next morning, the patient was alert and was extubated without difficulty. Steroids were tapered without hemodynamic compromise while the patient was in the ICU. Cardiology examination revealed no abnormalities. Because of the temporal association of blood transfusion with cardiovascular collapse, pRBC units were retested for antibodies and cultured. Both of these investigations were negative. Wound cultures again were positive for Staphylococcus epidermidis, and blood cultures were negative. The patient was started on daptomycin based on susceptibility profiles. Serum histamine levels taken during initial resuscitation in the operating room were normal. The serum tryptase level obtained at the same time was markedly elevated at >700 ng/mL (normal, <11.5 ng/mL), although this information was not available until several days later.

The patient underwent 2 additional surgeries during the same admission, including the prosthesis removal and tobramycin cement spacer placement, without incident. She was discharged home, again without incident. The patient was later evaluated by an outside allergist and underwent skin puncture and intradermal allergy testing. The results were consistent with a strong IgE-mediated hypersensitivity. Interestingly, she was found not to have a penicillin allergy.

Discussion

Vancomycin hypersensitivity reactions include the anaphylactoid reaction red man syndrome and a true IgE-mediated anaphylactic reaction. Red man syndrome is much more common, with reported rates in infected patients from 3.7% to 47%,^4,5 when vancomycin is given at the suggested  rate of 1 g over 1 hour. The reaction occurs because of histamine release from mast cells and basophils, and does not require previous sensitization.³ The rate of infusion is directly related to the development of symptoms, with 100% of patients developing symptoms in 1 study with rapid infusion (1 g over 10 min).⁶ Red man syndrome can typically be prevented by slowing the rate of infusion or by giving an H₁ blocker.³ Anaphylaxis is more rare but can occur.⁷ Anaphylaxis is mediated by vancomycin-specific IgE, which requires previous exposure, as was the case with our patient. Interestingly, the patient had received vancomycin many times without any signs of a hypersensitivity reaction. Antihistamines are not effective in treating anaphylaxis, and epinephrine is the first-line agent.³ This was clearly demonstrated in this case, as there was a significant hemodynamic response to epinephrine and a negligible response to other vasopressors, specifically norepinephrine and vasopressin.

Most hypersensitivity reactions during the course of a surgical procedure occur with induction of anesthesia, with neuromuscular blocking agents and antibiotics being the most common causes.⁸ In our case, antibiotics were held until after deep cultures were taken. Given the time from induction to the anaphylactic reaction, it is unlikely the reaction resulted from the induction agents or the neuromuscular blocking agent. The possibility of a transfusion reaction was also investigated, since a unit of pRBC was still being transfused when symptoms began. An acute hemolytic transfusion reaction has the classic triad of fever, flank pain, and hemoglobinuria, and can also present as DIC.⁹ Under anesthesia, DIC can often be the presenting sign. In this case, a hemolytic transfusion reaction appeared very unlikely. All of the blood components the patient received were rechecked and found to be compatible, posttransfusion analysis showed no evidence of hemolysis in any sample, and the direct antiglobulin test was negative in all components.

To our knowledge, there are no reported cases of vancomycin-induced anaphylaxis with concomitant DIC. Symptoms of anaphylaxis after exposure to a possible antigen include rapid onset of hypotension or rapid onset of signs in at least 2 organ systems, including cutaneous, gastrointestinal, respiratory, and cardiovascular.¹⁰ Anaphylaxis with DIC is rare after exposure to any substance but has been reported.¹¹ In fact, induction of systemic anaphylaxis in mice is known to cause DIC, with platelet-activating factor suggested as an important common mediator. A similar mechanism is suspected in humans.¹²

Confirmation of, and, certainly, prediction of, a vancomycin hypersensitivity reaction is difficult. Histamine levels can be used as a measure of mast-cell degranulation, but serum levels peak within 5 minutes and quickly return to baseline, limiting its diagnostic usefulness.³ Tryptase is an enzyme found in the secretory granules of mast cells. It has become an accepted marker of acute anaphylaxis, and, in vancomycin hypersensitivity reactions, can also distinguish between anaphylactic and anaphylactoid reactions.¹³ Tryptase levels peak 1 to 2 hours after the reaction, making this easier to measure than histamine, but results may not be available for several days, making it useful only in retrospect, as in our case. Skin testing is probably the best way to confirm a hypersensitivity reaction, although even this has been questioned with vancomycin because some find a high false-positive rate³, while others think the false-negative rate is likely too high.⁷ In this case, we were able to confirm our initial clinical suspicion with both an elevated tryptase level and a positive skin test.

Conclusion

We present a rare case of vancomycin anaphylaxis with DIC after repeated and prolonged previous exposure, which was treated acutely with hemodynamic resuscitation, replacement of blood components, steroids, and, most importantly, repeated boluses of epinephrine. Although several papers have described successful vancomycin desensitization⁷, this was fortunately not necessary in this case because the causative organism was sensitive to other acceptable antibiotics. The patient has been treated with systemic daptomycin and a tobramycin cement spacer without further incident.

An analysis of more than 50,000 patients with head and neck squamous cell carcinoma (HNSCC) found that prolonged time to treatment initiation (TTI) was an independent predictor of worse mortality.

Median overall survival for TTI of 67 days or fewer was 71 months compared with 49 months for TTI less than 67 days (P less than .001). For TTI of 46 to 52 days, median overall survival (OS) was 72 months; for TTI of 53 to 67 days, 61 months, and for TTI of greater than 67 days, 47 months (P less than .001).

The results provide strong evidence that “TTI greater than 67 days is too long and should be considered unacceptable,” wrote Dr. Colin Murphy, a radiation oncologist at Fox Chase Cancer Center, Philadelphia, and his colleagues.

“The current analysis suggests that increasing TTI beyond the threshold established in this monograph alters HNSCC survival and represents a public health issue,” the researchers stated (J Clin Onc. 2015 Dec 2. doi: 10.1200/JCO.2015.5906).

Data from the National Cancer Data Base pertained to 51,655 patients with head and neck squamous cell carcinoma, including oral tongue, oropharynx, larynx, and hypopharynx, during 1998-2011; median follow-up time was 84 months.

Academic institutions had significantly higher median TTI (28 days), compared with community programs (22-23 days), probably because of patients transitioning care, which was an independently associated factor in higher TTI. Despite higher median TTI, academic institutions were associated with improved overall survival, compared with community hospitals, as were care transitions.

Despite rapid tumor proliferation in HNSCC that can result in stage progression, 9.6% of all patients in 2011 had TTI of greater than 67 days, and 25% (29% at academic institutions) had TTI of greater than 46 days, another benchmark level identified in the study.

Mortality risk, according to TTI, was greater for patients with stage I or II disease, compared with stage III or IV disease, a finding that may be because of lymph node involvement. Development of nodal disease at stage III is a significant risk factor for mortality.

The investigators note that health systems elsewhere, in Denmark for example, have addressed the problem of prolonged TTI. Such efforts require coordination among providers and mandate expedited appointments for a patients with a new cancer diagnosis.

“Recently piloted programs offering next-day appointments with cancer specialists address this reversible predictor of mortality and may partially alleviate increasing TTI. Without such reforms, it is conceivable that outcomes will continue to worsen because of prolonged TTI,” they wrote.

An analysis of more than 50,000 patients with head and neck squamous cell carcinoma (HNSCC) found that prolonged time to treatment initiation (TTI) was an independent predictor of worse mortality.

Median overall survival for TTI of 67 days or fewer was 71 months compared with 49 months for TTI less than 67 days (P less than .001). For TTI of 46 to 52 days, median overall survival (OS) was 72 months; for TTI of 53 to 67 days, 61 months, and for TTI of greater than 67 days, 47 months (P less than .001).

The results provide strong evidence that “TTI greater than 67 days is too long and should be considered unacceptable,” wrote Dr. Colin Murphy, a radiation oncologist at Fox Chase Cancer Center, Philadelphia, and his colleagues.

“The current analysis suggests that increasing TTI beyond the threshold established in this monograph alters HNSCC survival and represents a public health issue,” the researchers stated (J Clin Onc. 2015 Dec 2. doi: 10.1200/JCO.2015.5906).

Data from the National Cancer Data Base pertained to 51,655 patients with head and neck squamous cell carcinoma, including oral tongue, oropharynx, larynx, and hypopharynx, during 1998-2011; median follow-up time was 84 months.

Academic institutions had significantly higher median TTI (28 days), compared with community programs (22-23 days), probably because of patients transitioning care, which was an independently associated factor in higher TTI. Despite higher median TTI, academic institutions were associated with improved overall survival, compared with community hospitals, as were care transitions.

Despite rapid tumor proliferation in HNSCC that can result in stage progression, 9.6% of all patients in 2011 had TTI of greater than 67 days, and 25% (29% at academic institutions) had TTI of greater than 46 days, another benchmark level identified in the study.

Mortality risk, according to TTI, was greater for patients with stage I or II disease, compared with stage III or IV disease, a finding that may be because of lymph node involvement. Development of nodal disease at stage III is a significant risk factor for mortality.

The investigators note that health systems elsewhere, in Denmark for example, have addressed the problem of prolonged TTI. Such efforts require coordination among providers and mandate expedited appointments for a patients with a new cancer diagnosis.

“Recently piloted programs offering next-day appointments with cancer specialists address this reversible predictor of mortality and may partially alleviate increasing TTI. Without such reforms, it is conceivable that outcomes will continue to worsen because of prolonged TTI,” they wrote.

An analysis of more than 50,000 patients with head and neck squamous cell carcinoma (HNSCC) found that prolonged time to treatment initiation (TTI) was an independent predictor of worse mortality.

Median overall survival for TTI of 67 days or fewer was 71 months compared with 49 months for TTI less than 67 days (P less than .001). For TTI of 46 to 52 days, median overall survival (OS) was 72 months; for TTI of 53 to 67 days, 61 months, and for TTI of greater than 67 days, 47 months (P less than .001).

The results provide strong evidence that “TTI greater than 67 days is too long and should be considered unacceptable,” wrote Dr. Colin Murphy, a radiation oncologist at Fox Chase Cancer Center, Philadelphia, and his colleagues.

“The current analysis suggests that increasing TTI beyond the threshold established in this monograph alters HNSCC survival and represents a public health issue,” the researchers stated (J Clin Onc. 2015 Dec 2. doi: 10.1200/JCO.2015.5906).

Data from the National Cancer Data Base pertained to 51,655 patients with head and neck squamous cell carcinoma, including oral tongue, oropharynx, larynx, and hypopharynx, during 1998-2011; median follow-up time was 84 months.

Academic institutions had significantly higher median TTI (28 days), compared with community programs (22-23 days), probably because of patients transitioning care, which was an independently associated factor in higher TTI. Despite higher median TTI, academic institutions were associated with improved overall survival, compared with community hospitals, as were care transitions.

Despite rapid tumor proliferation in HNSCC that can result in stage progression, 9.6% of all patients in 2011 had TTI of greater than 67 days, and 25% (29% at academic institutions) had TTI of greater than 46 days, another benchmark level identified in the study.

Mortality risk, according to TTI, was greater for patients with stage I or II disease, compared with stage III or IV disease, a finding that may be because of lymph node involvement. Development of nodal disease at stage III is a significant risk factor for mortality.

The investigators note that health systems elsewhere, in Denmark for example, have addressed the problem of prolonged TTI. Such efforts require coordination among providers and mandate expedited appointments for a patients with a new cancer diagnosis.

“Recently piloted programs offering next-day appointments with cancer specialists address this reversible predictor of mortality and may partially alleviate increasing TTI. Without such reforms, it is conceivable that outcomes will continue to worsen because of prolonged TTI,” they wrote.

Necrotizing fasciitis (NF) is a severe, rapidly spreading soft-tissue infection with high morbidity and mortality. Bacteriology in NF may be varied, and the etiology is often polymicrobial. It is important to consider the potential for fungal involvement despite its rarity. Cryptococcal NF has been reported in immunocompromised patients, with Cryptococcus neoformans being the most common offending organism.^1-4

C neoformans is a basidiomycotic yeast that was previously considered a homogenous species.^5,6 From the antigenic properties of its polysaccharide capsule, 3 main variants were described: C neoformans var. grubii, C neoformans var. neoformans, and C neoformans var. gattii. Subsequently, C neoformans var. gattii was found to be genetically and biochemically different from C neoformans. This discovery led to the distinction of C neoformans var. gattii as a separate species and it being renamed C gattii.⁶

C gattii was first recognized on Vancouver Island in 2001.⁷ Although C gattii is predominantly restricted to tropical and subtropical climates, its true epidemiology has been limited by diagnostic methods. C gattii can be diagnosed with laboratory culture media such as birdseed agars and L-canavanine-glycine-bromothymol (CGB) agar.⁶ However, most reports of Cryptococcus NF do not specify the culture media used to isolate Cryptococcus. In addition to culture media, molecular genotyping studies also allow for confirmation of the diagnosis of C gattii and have the added benefit of enabling identification of the molecular genotype. Nonetheless, in many clinical microbiology laboratories, Cryptococcus is not identified to the species level, much less to the molecular genotype.⁷ Given these diagnostic limitations and the fact that C gattii was only recently identified as a separate species, it is possible that any pre-2006 cases of NF attributed to C neoformans could in fact have been caused by C gattii.

In this article, we review the literature and report a case of NF of the hand that was caused by C gattii in a patient with diabetes. To our knowledge, this is the first reported case of NF caused by C gattii. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 73-year-old man was admitted with a 1-week history of swelling and pain in the dorsum of the left hand. He had been sitting in an outdoor eatery in Singapore when an insect bit the hand over the dorsum. Two days later, he consulted his family physician, who began treatment with oral amoxicillin/clavulanic acid. After 4 days of treatment, there was clinical progression of increased swelling and pain in the hand. Six days after initial injury, the patient presented to the department of orthopedic surgery.

Physical examination revealed diffuse, brawny, nonfluctuant swelling over the entire dorsum of the left hand (Figure 1). There was a 1×1-cm ruptured blister with some nonpurulent discharge just distal to the wrist joint. Neurovascular status and the extensor mechanism of the fingers were intact. The wrist joint had full range of motion. There was no fever.

Laboratory testing revealed an elevated white blood cell count (16.6×10⁹/L), a C-reactive protein (CRP) level of 237 nmol/L, a random blood glucose level of 12.6 mmol/L, and a LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) score of 7.⁸

Given the severe swelling, intravenous amoxicillin/clavulanic acid was started. The patient received a total of 3 doses before operative débridement of the left hand. Operative findings were NF of the hand, grayish necrotic fascia, and foul-smelling “dishwater” fluid. A single specimen of fascia from the surgical site was sent for examination. Histopathologic examination of formalin-fixed, paraffin-embedded tissue revealed necrotizing suppurative inflammation with fungal organisms present (Figures 2, 3).

Tissue cultures were obtained during surgery. The organism grew as scanty, small, wet-looking colonies on sheep blood agar after 48 hours of incubation. Microscopy revealed an oval yeast. The organism was identified and reported as C gattii by matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS; Biotyper 2.0.1 software; Bruker Daltonics), with a score of 1.914.⁹ All other intraoperative cultures for aerobic and anaerobic bacteria were negative. Molecular genotyping was performed with polymerase chain reaction assay to identify the molecular subtype.¹⁰C gattii genotype VGII was isolated. A cryptococcal serum antigen assay was positive at 1:256.

A series of tests was performed to screen for disseminated disease. Blood cultures were negative for fungus. Chest radiography and computed tomography of the brain did not show any pulmonary or cerebral involvement. Cerebrospinal fluid was not available for examination, as the patient declined lumbar puncture. Blood tests included a negative result for human immunodeficiency virus (HIV). The patient was found to have previously undiagnosed diabetes mellitus (hemoglobin A_1c, 7.9%). T-cell counts and ratios were normal.

The patient was started on intravenous amphotericin B 60 mg/d and flucytosine 500 mg every 6 hours for 3 weeks. Oral fluconazole 400 mg every morning was also given (intended duration, 6 mo). Given that diabetes was newly diagnosed, the patient was treated with metformin; his capillary blood glucose level remained stable during his inpatient stay.

Four débridements of the dorsal hand wound were performed—the first on day of admission and the other 3 on hospitalization days 3, 7, and 18 (Figure 4). Subsequent wound resurfacing with a split skin graft harvested from the forearm was performed on hospitalization day 22. After surgery, the hand was dressed with a bulky cotton dressing. Five days after the patient was discharged, during review in the outpatient clinic, the skin graft was noted to be taking well. The patient did not attend postoperative physical therapy. He was maintained on metformin and given a follow-up clinic appointment for his diabetes. Four months after surgery, the wound was completely healed, and normal functional use of the hand recovered.

Discussion

NF is a severe soft-tissue infection with potential for rapid progression. Surgical débridement should be performed urgently to reduce the chance of morbidity and mortality.¹¹ The initial classification by Giuliano and colleagues¹² was based on bacteriology and included type I (anaerobic species in combination with a facultative species) and type II (monomicrobial usually involving group A β-hemolytic Streptococcus). This classification was modified by Morgan¹³ to include gram-negative organisms as well as fungal organisms (Table 1).

Fungal NF is rare, with Candida, Apophysomyces, and Cryptococcus described in the literature.^1,14,15 Fungal infections tend to occur in immunocompromised patients; risk factors are steroid immunosuppression, poorly controlled diabetes, and peripheral vascular disease.¹⁶ Some zygomycetes may also affect immunocompetent patients.¹⁵

C gattii is an encapsulated yeast organism that is genetically and biochemically distinct from C neoformans. It is endemic to tropical parts of Africa and Australia. Its main environmental sources are eucalyptus trees (Eucalyptus camaldulensis, Eucalyptus tereticornis) and decaying hollows in living trees.¹⁷ In addition, there have been reports of isolation of C gattii from insect frass,¹⁸ which would make infection by an insect bite a possible transmission route. Worldwide distribution of this pathogen has increased recently, with outbreaks noted on Vancouver Island and in areas in Canada and the northwest United States.⁷

The true incidence of NF secondary to C gattii is difficult to determine. C gattii was only recently identified as a separate species, and pre-2006 cases of NF attributed to C neoformans may instead have been caused by C gattii. Misidentification has been compounded by the fact that the tests required for accurate diagnosis of C gattii infection may not be readily available in many clinical microbiology laboratories. Cryptococcus can be identified with various methods, including direct microscopy, culturing of tissue or fluid samples, and measurement of cryptococcal serum antigen. However, tests such as specific culture media, mass spectrometry, and molecular typing studies are required to determine cryptococcal species. L-canavanine-glycine-bromothymol blue (CGB) agar is a medium that is often used to differentiate C gattii from C neoformans because of the ability of C gattii to produce a blue appearance.⁶ Modern techniques, such as MALDI-TOF MS, have also been used to successfully distinguish between C gattii and C neoformans.⁹ MALDI-TOF MS identifies species on the basis of characteristic protein spectra extracted from whole cells. Using commercial and supplemental reference libraries, the system compares signal matches in the reference spectrum with Cryptococcus entries in the library—allowing rapid and accurate identification of cryptococcal species. However, this diagnostic method is limited by availability of adequate Cryptococcus entries in the reference library and by the high cost of acquiring the machine.

Serotyping is based on the antigenic property of the capsule and was once used to differentiate C neoformans into its 3 main varieties: var. neoformans, var. grubii, var. gattii. However, when it was realized that the antigenic property of the strain can be unstable and that there are hybrids containing more than 1 serotype, serotyping was abandoned as a species-differentiation test.⁶ The current gold standard for species differentiation is molecular genotyping. Molecular genotyping studies can confirm the diagnosis of C gattii infection and allow differentiation of C gattii into its 4 main molecular types: VGI, VGII, VGIII, VGIV. Using methods such as polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis, molecular typing allows for specific epidemiology charting of C gattii genotypes.⁷

Although the transmission route for cryptococcal infection is mainly respiratory, direct inoculation has been reported as well.¹⁹ Cutaneous lesions, which occur in 5% to 20% of cryptococcal infections, often present in the head and neck.^2,20,21 Primary cutaneous infections from cryptococcosis are rare, and cutaneous manifestations are often a sign of disseminated disease. Disseminated disease is defined as the involvement of 2 or more noncontiguous sites or evidence of high fungal burden based on cryptococcal antigen titer of more than 1:512.¹² It is important to exclude disseminated disease in all cases of cryptococcosis, as it may be fatal.²⁰ The neural and pulmonary systems should be screened.²² Cellulitis from cryptococcosis is almost always limited to immunocompromised patients, though there are reports of crytococcal cutaneous disease in immunocompetent patients.^3,15 Interestingly, though C neoformans often affects immunocompromised patients, the emerging pathogen of C gattii affects immunocompetent patients.^7,17,23 Our patient’s undiagnosed diabetes may have been a risk factor for cryptococcal infection. His cryptococcal antigen titer was 1:256, with no evidence of other sites of involvement. We therefore believe this to be a rare case of direct inoculation secondary to an insect bite.

The literature includes 12 reported cases of NF secondary to Cryptococcus (Table 2), all C neoformans. Of these cases, 9 involved immunosuppression, and most of these patients were on long-term steroid treatment after organ transplantation. The most common infection site was the lower extremity. These cases of cryptococcal NF show that immunosuppression, and long-term steroid use in particular, is an important risk factor. The mortality rate for these reviewed cases was 41.6% (5/12). According to the literature, the mortality rates for patients with cryptococcal soft-tissue infections²⁴ and posttransplant patients with cryptococcal NF²¹ were 37.5% and 60%, respectively. We believe the mortality rate in our reviewed cases likely was confounded by the fact that most of the patients were posttransplant patients on long-term immunosuppression.

Of the 12 patients, 5 had primary cutaneous disease. There seems to be no relationship between outcome and dissemination of disease. In addition, there is a paucity of literature on the effect of disseminated disease and cryptococcal soft-tissue infections. Therefore, no firm conclusions can be drawn regarding the effects of disseminated disease on severity of cryptococcal soft-tissue infection.

Treatment of cryptococcal NF involves a combination of surgical débridement and long-term antifungal therapy. Surgical débridement of NF includes delineating the extent of infection with complete surgical excision of the affected tissue.²⁵ The aims of surgery should be to remove all unhealthy tissue, identify the offending organism, and plan for resurfacing or reconstruction of the afflicted extremity. Intraoperative-tissue histology should be performed to confirm the diagnosis of NF. Histology can be used to demonstrate cryptococcal infection. The diagnosis of cryptococcal infection can be aided with fungal cultures, and therefore we recommend that tissue cultures be sent not only for routine aerobic/anaerobic bacteria but also for mycobacteria and fungal organisms. Laboratory tests that aid in diagnosis include serum cryptococcal antigen titer.

The current treatment recommendation for cryptococcal disease in patients who are not HIV-positive or transplant hosts is amphotericin B deoxycholate 0.7 to 1.0 mg/kg/d plus flucytosine 100 mg/kg/d for at least 4 weeks.²² The regimen period may be shortened to 14 days for patients at low risk of treatment failure. Fluconazole should be given as maintenance therapy (200 mg/d) for 6 to 12 months. There is no compelling evidence for immunoglobulin therapy for cryptococcal disease.²²

Conclusion

NF caused by Cryptococcus is rare. A high level of suspicion, and intraoperative specimens for histology and fungal microscopy and culture, can help in establishing the diagnosis. Molecular genotyping remains the diagnostic method of choice for NF secondary to Cryptococcus. Effective treatment consists of aggressive surgical débridement and antifungal therapy.

Necrotizing fasciitis (NF) is a severe, rapidly spreading soft-tissue infection with high morbidity and mortality. Bacteriology in NF may be varied, and the etiology is often polymicrobial. It is important to consider the potential for fungal involvement despite its rarity. Cryptococcal NF has been reported in immunocompromised patients, with Cryptococcus neoformans being the most common offending organism.^1-4

C neoformans is a basidiomycotic yeast that was previously considered a homogenous species.^5,6 From the antigenic properties of its polysaccharide capsule, 3 main variants were described: C neoformans var. grubii, C neoformans var. neoformans, and C neoformans var. gattii. Subsequently, C neoformans var. gattii was found to be genetically and biochemically different from C neoformans. This discovery led to the distinction of C neoformans var. gattii as a separate species and it being renamed C gattii.⁶

C gattii was first recognized on Vancouver Island in 2001.⁷ Although C gattii is predominantly restricted to tropical and subtropical climates, its true epidemiology has been limited by diagnostic methods. C gattii can be diagnosed with laboratory culture media such as birdseed agars and L-canavanine-glycine-bromothymol (CGB) agar.⁶ However, most reports of Cryptococcus NF do not specify the culture media used to isolate Cryptococcus. In addition to culture media, molecular genotyping studies also allow for confirmation of the diagnosis of C gattii and have the added benefit of enabling identification of the molecular genotype. Nonetheless, in many clinical microbiology laboratories, Cryptococcus is not identified to the species level, much less to the molecular genotype.⁷ Given these diagnostic limitations and the fact that C gattii was only recently identified as a separate species, it is possible that any pre-2006 cases of NF attributed to C neoformans could in fact have been caused by C gattii.

In this article, we review the literature and report a case of NF of the hand that was caused by C gattii in a patient with diabetes. To our knowledge, this is the first reported case of NF caused by C gattii. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 73-year-old man was admitted with a 1-week history of swelling and pain in the dorsum of the left hand. He had been sitting in an outdoor eatery in Singapore when an insect bit the hand over the dorsum. Two days later, he consulted his family physician, who began treatment with oral amoxicillin/clavulanic acid. After 4 days of treatment, there was clinical progression of increased swelling and pain in the hand. Six days after initial injury, the patient presented to the department of orthopedic surgery.

Physical examination revealed diffuse, brawny, nonfluctuant swelling over the entire dorsum of the left hand (Figure 1). There was a 1×1-cm ruptured blister with some nonpurulent discharge just distal to the wrist joint. Neurovascular status and the extensor mechanism of the fingers were intact. The wrist joint had full range of motion. There was no fever.

Laboratory testing revealed an elevated white blood cell count (16.6×10⁹/L), a C-reactive protein (CRP) level of 237 nmol/L, a random blood glucose level of 12.6 mmol/L, and a LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) score of 7.⁸

Given the severe swelling, intravenous amoxicillin/clavulanic acid was started. The patient received a total of 3 doses before operative débridement of the left hand. Operative findings were NF of the hand, grayish necrotic fascia, and foul-smelling “dishwater” fluid. A single specimen of fascia from the surgical site was sent for examination. Histopathologic examination of formalin-fixed, paraffin-embedded tissue revealed necrotizing suppurative inflammation with fungal organisms present (Figures 2, 3).

Tissue cultures were obtained during surgery. The organism grew as scanty, small, wet-looking colonies on sheep blood agar after 48 hours of incubation. Microscopy revealed an oval yeast. The organism was identified and reported as C gattii by matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS; Biotyper 2.0.1 software; Bruker Daltonics), with a score of 1.914.⁹ All other intraoperative cultures for aerobic and anaerobic bacteria were negative. Molecular genotyping was performed with polymerase chain reaction assay to identify the molecular subtype.¹⁰C gattii genotype VGII was isolated. A cryptococcal serum antigen assay was positive at 1:256.

A series of tests was performed to screen for disseminated disease. Blood cultures were negative for fungus. Chest radiography and computed tomography of the brain did not show any pulmonary or cerebral involvement. Cerebrospinal fluid was not available for examination, as the patient declined lumbar puncture. Blood tests included a negative result for human immunodeficiency virus (HIV). The patient was found to have previously undiagnosed diabetes mellitus (hemoglobin A_1c, 7.9%). T-cell counts and ratios were normal.

The patient was started on intravenous amphotericin B 60 mg/d and flucytosine 500 mg every 6 hours for 3 weeks. Oral fluconazole 400 mg every morning was also given (intended duration, 6 mo). Given that diabetes was newly diagnosed, the patient was treated with metformin; his capillary blood glucose level remained stable during his inpatient stay.

Four débridements of the dorsal hand wound were performed—the first on day of admission and the other 3 on hospitalization days 3, 7, and 18 (Figure 4). Subsequent wound resurfacing with a split skin graft harvested from the forearm was performed on hospitalization day 22. After surgery, the hand was dressed with a bulky cotton dressing. Five days after the patient was discharged, during review in the outpatient clinic, the skin graft was noted to be taking well. The patient did not attend postoperative physical therapy. He was maintained on metformin and given a follow-up clinic appointment for his diabetes. Four months after surgery, the wound was completely healed, and normal functional use of the hand recovered.

Discussion

NF is a severe soft-tissue infection with potential for rapid progression. Surgical débridement should be performed urgently to reduce the chance of morbidity and mortality.¹¹ The initial classification by Giuliano and colleagues¹² was based on bacteriology and included type I (anaerobic species in combination with a facultative species) and type II (monomicrobial usually involving group A β-hemolytic Streptococcus). This classification was modified by Morgan¹³ to include gram-negative organisms as well as fungal organisms (Table 1).

Fungal NF is rare, with Candida, Apophysomyces, and Cryptococcus described in the literature.^1,14,15 Fungal infections tend to occur in immunocompromised patients; risk factors are steroid immunosuppression, poorly controlled diabetes, and peripheral vascular disease.¹⁶ Some zygomycetes may also affect immunocompetent patients.¹⁵

C gattii is an encapsulated yeast organism that is genetically and biochemically distinct from C neoformans. It is endemic to tropical parts of Africa and Australia. Its main environmental sources are eucalyptus trees (Eucalyptus camaldulensis, Eucalyptus tereticornis) and decaying hollows in living trees.¹⁷ In addition, there have been reports of isolation of C gattii from insect frass,¹⁸ which would make infection by an insect bite a possible transmission route. Worldwide distribution of this pathogen has increased recently, with outbreaks noted on Vancouver Island and in areas in Canada and the northwest United States.⁷

The true incidence of NF secondary to C gattii is difficult to determine. C gattii was only recently identified as a separate species, and pre-2006 cases of NF attributed to C neoformans may instead have been caused by C gattii. Misidentification has been compounded by the fact that the tests required for accurate diagnosis of C gattii infection may not be readily available in many clinical microbiology laboratories. Cryptococcus can be identified with various methods, including direct microscopy, culturing of tissue or fluid samples, and measurement of cryptococcal serum antigen. However, tests such as specific culture media, mass spectrometry, and molecular typing studies are required to determine cryptococcal species. L-canavanine-glycine-bromothymol blue (CGB) agar is a medium that is often used to differentiate C gattii from C neoformans because of the ability of C gattii to produce a blue appearance.⁶ Modern techniques, such as MALDI-TOF MS, have also been used to successfully distinguish between C gattii and C neoformans.⁹ MALDI-TOF MS identifies species on the basis of characteristic protein spectra extracted from whole cells. Using commercial and supplemental reference libraries, the system compares signal matches in the reference spectrum with Cryptococcus entries in the library—allowing rapid and accurate identification of cryptococcal species. However, this diagnostic method is limited by availability of adequate Cryptococcus entries in the reference library and by the high cost of acquiring the machine.

Serotyping is based on the antigenic property of the capsule and was once used to differentiate C neoformans into its 3 main varieties: var. neoformans, var. grubii, var. gattii. However, when it was realized that the antigenic property of the strain can be unstable and that there are hybrids containing more than 1 serotype, serotyping was abandoned as a species-differentiation test.⁶ The current gold standard for species differentiation is molecular genotyping. Molecular genotyping studies can confirm the diagnosis of C gattii infection and allow differentiation of C gattii into its 4 main molecular types: VGI, VGII, VGIII, VGIV. Using methods such as polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis, molecular typing allows for specific epidemiology charting of C gattii genotypes.⁷

Although the transmission route for cryptococcal infection is mainly respiratory, direct inoculation has been reported as well.¹⁹ Cutaneous lesions, which occur in 5% to 20% of cryptococcal infections, often present in the head and neck.^2,20,21 Primary cutaneous infections from cryptococcosis are rare, and cutaneous manifestations are often a sign of disseminated disease. Disseminated disease is defined as the involvement of 2 or more noncontiguous sites or evidence of high fungal burden based on cryptococcal antigen titer of more than 1:512.¹² It is important to exclude disseminated disease in all cases of cryptococcosis, as it may be fatal.²⁰ The neural and pulmonary systems should be screened.²² Cellulitis from cryptococcosis is almost always limited to immunocompromised patients, though there are reports of crytococcal cutaneous disease in immunocompetent patients.^3,15 Interestingly, though C neoformans often affects immunocompromised patients, the emerging pathogen of C gattii affects immunocompetent patients.^7,17,23 Our patient’s undiagnosed diabetes may have been a risk factor for cryptococcal infection. His cryptococcal antigen titer was 1:256, with no evidence of other sites of involvement. We therefore believe this to be a rare case of direct inoculation secondary to an insect bite.

The literature includes 12 reported cases of NF secondary to Cryptococcus (Table 2), all C neoformans. Of these cases, 9 involved immunosuppression, and most of these patients were on long-term steroid treatment after organ transplantation. The most common infection site was the lower extremity. These cases of cryptococcal NF show that immunosuppression, and long-term steroid use in particular, is an important risk factor. The mortality rate for these reviewed cases was 41.6% (5/12). According to the literature, the mortality rates for patients with cryptococcal soft-tissue infections²⁴ and posttransplant patients with cryptococcal NF²¹ were 37.5% and 60%, respectively. We believe the mortality rate in our reviewed cases likely was confounded by the fact that most of the patients were posttransplant patients on long-term immunosuppression.

Of the 12 patients, 5 had primary cutaneous disease. There seems to be no relationship between outcome and dissemination of disease. In addition, there is a paucity of literature on the effect of disseminated disease and cryptococcal soft-tissue infections. Therefore, no firm conclusions can be drawn regarding the effects of disseminated disease on severity of cryptococcal soft-tissue infection.

Treatment of cryptococcal NF involves a combination of surgical débridement and long-term antifungal therapy. Surgical débridement of NF includes delineating the extent of infection with complete surgical excision of the affected tissue.²⁵ The aims of surgery should be to remove all unhealthy tissue, identify the offending organism, and plan for resurfacing or reconstruction of the afflicted extremity. Intraoperative-tissue histology should be performed to confirm the diagnosis of NF. Histology can be used to demonstrate cryptococcal infection. The diagnosis of cryptococcal infection can be aided with fungal cultures, and therefore we recommend that tissue cultures be sent not only for routine aerobic/anaerobic bacteria but also for mycobacteria and fungal organisms. Laboratory tests that aid in diagnosis include serum cryptococcal antigen titer.

The current treatment recommendation for cryptococcal disease in patients who are not HIV-positive or transplant hosts is amphotericin B deoxycholate 0.7 to 1.0 mg/kg/d plus flucytosine 100 mg/kg/d for at least 4 weeks.²² The regimen period may be shortened to 14 days for patients at low risk of treatment failure. Fluconazole should be given as maintenance therapy (200 mg/d) for 6 to 12 months. There is no compelling evidence for immunoglobulin therapy for cryptococcal disease.²²

Conclusion

NF caused by Cryptococcus is rare. A high level of suspicion, and intraoperative specimens for histology and fungal microscopy and culture, can help in establishing the diagnosis. Molecular genotyping remains the diagnostic method of choice for NF secondary to Cryptococcus. Effective treatment consists of aggressive surgical débridement and antifungal therapy.

Necrotizing fasciitis (NF) is a severe, rapidly spreading soft-tissue infection with high morbidity and mortality. Bacteriology in NF may be varied, and the etiology is often polymicrobial. It is important to consider the potential for fungal involvement despite its rarity. Cryptococcal NF has been reported in immunocompromised patients, with Cryptococcus neoformans being the most common offending organism.^1-4

C neoformans is a basidiomycotic yeast that was previously considered a homogenous species.^5,6 From the antigenic properties of its polysaccharide capsule, 3 main variants were described: C neoformans var. grubii, C neoformans var. neoformans, and C neoformans var. gattii. Subsequently, C neoformans var. gattii was found to be genetically and biochemically different from C neoformans. This discovery led to the distinction of C neoformans var. gattii as a separate species and it being renamed C gattii.⁶

C gattii was first recognized on Vancouver Island in 2001.⁷ Although C gattii is predominantly restricted to tropical and subtropical climates, its true epidemiology has been limited by diagnostic methods. C gattii can be diagnosed with laboratory culture media such as birdseed agars and L-canavanine-glycine-bromothymol (CGB) agar.⁶ However, most reports of Cryptococcus NF do not specify the culture media used to isolate Cryptococcus. In addition to culture media, molecular genotyping studies also allow for confirmation of the diagnosis of C gattii and have the added benefit of enabling identification of the molecular genotype. Nonetheless, in many clinical microbiology laboratories, Cryptococcus is not identified to the species level, much less to the molecular genotype.⁷ Given these diagnostic limitations and the fact that C gattii was only recently identified as a separate species, it is possible that any pre-2006 cases of NF attributed to C neoformans could in fact have been caused by C gattii.

In this article, we review the literature and report a case of NF of the hand that was caused by C gattii in a patient with diabetes. To our knowledge, this is the first reported case of NF caused by C gattii. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 73-year-old man was admitted with a 1-week history of swelling and pain in the dorsum of the left hand. He had been sitting in an outdoor eatery in Singapore when an insect bit the hand over the dorsum. Two days later, he consulted his family physician, who began treatment with oral amoxicillin/clavulanic acid. After 4 days of treatment, there was clinical progression of increased swelling and pain in the hand. Six days after initial injury, the patient presented to the department of orthopedic surgery.

Physical examination revealed diffuse, brawny, nonfluctuant swelling over the entire dorsum of the left hand (Figure 1). There was a 1×1-cm ruptured blister with some nonpurulent discharge just distal to the wrist joint. Neurovascular status and the extensor mechanism of the fingers were intact. The wrist joint had full range of motion. There was no fever.

Laboratory testing revealed an elevated white blood cell count (16.6×10⁹/L), a C-reactive protein (CRP) level of 237 nmol/L, a random blood glucose level of 12.6 mmol/L, and a LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) score of 7.⁸

Given the severe swelling, intravenous amoxicillin/clavulanic acid was started. The patient received a total of 3 doses before operative débridement of the left hand. Operative findings were NF of the hand, grayish necrotic fascia, and foul-smelling “dishwater” fluid. A single specimen of fascia from the surgical site was sent for examination. Histopathologic examination of formalin-fixed, paraffin-embedded tissue revealed necrotizing suppurative inflammation with fungal organisms present (Figures 2, 3).

Tissue cultures were obtained during surgery. The organism grew as scanty, small, wet-looking colonies on sheep blood agar after 48 hours of incubation. Microscopy revealed an oval yeast. The organism was identified and reported as C gattii by matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS; Biotyper 2.0.1 software; Bruker Daltonics), with a score of 1.914.⁹ All other intraoperative cultures for aerobic and anaerobic bacteria were negative. Molecular genotyping was performed with polymerase chain reaction assay to identify the molecular subtype.¹⁰C gattii genotype VGII was isolated. A cryptococcal serum antigen assay was positive at 1:256.

A series of tests was performed to screen for disseminated disease. Blood cultures were negative for fungus. Chest radiography and computed tomography of the brain did not show any pulmonary or cerebral involvement. Cerebrospinal fluid was not available for examination, as the patient declined lumbar puncture. Blood tests included a negative result for human immunodeficiency virus (HIV). The patient was found to have previously undiagnosed diabetes mellitus (hemoglobin A_1c, 7.9%). T-cell counts and ratios were normal.

The patient was started on intravenous amphotericin B 60 mg/d and flucytosine 500 mg every 6 hours for 3 weeks. Oral fluconazole 400 mg every morning was also given (intended duration, 6 mo). Given that diabetes was newly diagnosed, the patient was treated with metformin; his capillary blood glucose level remained stable during his inpatient stay.

Four débridements of the dorsal hand wound were performed—the first on day of admission and the other 3 on hospitalization days 3, 7, and 18 (Figure 4). Subsequent wound resurfacing with a split skin graft harvested from the forearm was performed on hospitalization day 22. After surgery, the hand was dressed with a bulky cotton dressing. Five days after the patient was discharged, during review in the outpatient clinic, the skin graft was noted to be taking well. The patient did not attend postoperative physical therapy. He was maintained on metformin and given a follow-up clinic appointment for his diabetes. Four months after surgery, the wound was completely healed, and normal functional use of the hand recovered.

Discussion

NF is a severe soft-tissue infection with potential for rapid progression. Surgical débridement should be performed urgently to reduce the chance of morbidity and mortality.¹¹ The initial classification by Giuliano and colleagues¹² was based on bacteriology and included type I (anaerobic species in combination with a facultative species) and type II (monomicrobial usually involving group A β-hemolytic Streptococcus). This classification was modified by Morgan¹³ to include gram-negative organisms as well as fungal organisms (Table 1).

Fungal NF is rare, with Candida, Apophysomyces, and Cryptococcus described in the literature.^1,14,15 Fungal infections tend to occur in immunocompromised patients; risk factors are steroid immunosuppression, poorly controlled diabetes, and peripheral vascular disease.¹⁶ Some zygomycetes may also affect immunocompetent patients.¹⁵

C gattii is an encapsulated yeast organism that is genetically and biochemically distinct from C neoformans. It is endemic to tropical parts of Africa and Australia. Its main environmental sources are eucalyptus trees (Eucalyptus camaldulensis, Eucalyptus tereticornis) and decaying hollows in living trees.¹⁷ In addition, there have been reports of isolation of C gattii from insect frass,¹⁸ which would make infection by an insect bite a possible transmission route. Worldwide distribution of this pathogen has increased recently, with outbreaks noted on Vancouver Island and in areas in Canada and the northwest United States.⁷

The true incidence of NF secondary to C gattii is difficult to determine. C gattii was only recently identified as a separate species, and pre-2006 cases of NF attributed to C neoformans may instead have been caused by C gattii. Misidentification has been compounded by the fact that the tests required for accurate diagnosis of C gattii infection may not be readily available in many clinical microbiology laboratories. Cryptococcus can be identified with various methods, including direct microscopy, culturing of tissue or fluid samples, and measurement of cryptococcal serum antigen. However, tests such as specific culture media, mass spectrometry, and molecular typing studies are required to determine cryptococcal species. L-canavanine-glycine-bromothymol blue (CGB) agar is a medium that is often used to differentiate C gattii from C neoformans because of the ability of C gattii to produce a blue appearance.⁶ Modern techniques, such as MALDI-TOF MS, have also been used to successfully distinguish between C gattii and C neoformans.⁹ MALDI-TOF MS identifies species on the basis of characteristic protein spectra extracted from whole cells. Using commercial and supplemental reference libraries, the system compares signal matches in the reference spectrum with Cryptococcus entries in the library—allowing rapid and accurate identification of cryptococcal species. However, this diagnostic method is limited by availability of adequate Cryptococcus entries in the reference library and by the high cost of acquiring the machine.

Serotyping is based on the antigenic property of the capsule and was once used to differentiate C neoformans into its 3 main varieties: var. neoformans, var. grubii, var. gattii. However, when it was realized that the antigenic property of the strain can be unstable and that there are hybrids containing more than 1 serotype, serotyping was abandoned as a species-differentiation test.⁶ The current gold standard for species differentiation is molecular genotyping. Molecular genotyping studies can confirm the diagnosis of C gattii infection and allow differentiation of C gattii into its 4 main molecular types: VGI, VGII, VGIII, VGIV. Using methods such as polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis, molecular typing allows for specific epidemiology charting of C gattii genotypes.⁷

Although the transmission route for cryptococcal infection is mainly respiratory, direct inoculation has been reported as well.¹⁹ Cutaneous lesions, which occur in 5% to 20% of cryptococcal infections, often present in the head and neck.^2,20,21 Primary cutaneous infections from cryptococcosis are rare, and cutaneous manifestations are often a sign of disseminated disease. Disseminated disease is defined as the involvement of 2 or more noncontiguous sites or evidence of high fungal burden based on cryptococcal antigen titer of more than 1:512.¹² It is important to exclude disseminated disease in all cases of cryptococcosis, as it may be fatal.²⁰ The neural and pulmonary systems should be screened.²² Cellulitis from cryptococcosis is almost always limited to immunocompromised patients, though there are reports of crytococcal cutaneous disease in immunocompetent patients.^3,15 Interestingly, though C neoformans often affects immunocompromised patients, the emerging pathogen of C gattii affects immunocompetent patients.^7,17,23 Our patient’s undiagnosed diabetes may have been a risk factor for cryptococcal infection. His cryptococcal antigen titer was 1:256, with no evidence of other sites of involvement. We therefore believe this to be a rare case of direct inoculation secondary to an insect bite.

The literature includes 12 reported cases of NF secondary to Cryptococcus (Table 2), all C neoformans. Of these cases, 9 involved immunosuppression, and most of these patients were on long-term steroid treatment after organ transplantation. The most common infection site was the lower extremity. These cases of cryptococcal NF show that immunosuppression, and long-term steroid use in particular, is an important risk factor. The mortality rate for these reviewed cases was 41.6% (5/12). According to the literature, the mortality rates for patients with cryptococcal soft-tissue infections²⁴ and posttransplant patients with cryptococcal NF²¹ were 37.5% and 60%, respectively. We believe the mortality rate in our reviewed cases likely was confounded by the fact that most of the patients were posttransplant patients on long-term immunosuppression.

Of the 12 patients, 5 had primary cutaneous disease. There seems to be no relationship between outcome and dissemination of disease. In addition, there is a paucity of literature on the effect of disseminated disease and cryptococcal soft-tissue infections. Therefore, no firm conclusions can be drawn regarding the effects of disseminated disease on severity of cryptococcal soft-tissue infection.

Treatment of cryptococcal NF involves a combination of surgical débridement and long-term antifungal therapy. Surgical débridement of NF includes delineating the extent of infection with complete surgical excision of the affected tissue.²⁵ The aims of surgery should be to remove all unhealthy tissue, identify the offending organism, and plan for resurfacing or reconstruction of the afflicted extremity. Intraoperative-tissue histology should be performed to confirm the diagnosis of NF. Histology can be used to demonstrate cryptococcal infection. The diagnosis of cryptococcal infection can be aided with fungal cultures, and therefore we recommend that tissue cultures be sent not only for routine aerobic/anaerobic bacteria but also for mycobacteria and fungal organisms. Laboratory tests that aid in diagnosis include serum cryptococcal antigen titer.

The current treatment recommendation for cryptococcal disease in patients who are not HIV-positive or transplant hosts is amphotericin B deoxycholate 0.7 to 1.0 mg/kg/d plus flucytosine 100 mg/kg/d for at least 4 weeks.²² The regimen period may be shortened to 14 days for patients at low risk of treatment failure. Fluconazole should be given as maintenance therapy (200 mg/d) for 6 to 12 months. There is no compelling evidence for immunoglobulin therapy for cryptococcal disease.²²

Conclusion

NF caused by Cryptococcus is rare. A high level of suspicion, and intraoperative specimens for histology and fungal microscopy and culture, can help in establishing the diagnosis. Molecular genotyping remains the diagnostic method of choice for NF secondary to Cryptococcus. Effective treatment consists of aggressive surgical débridement and antifungal therapy.

With an incidence of 75,000 per year in the United States alone, fractures of the tibial shaft are among the most common long-bone fractures.¹ Diaphyseal tibial fractures present a unique treatment challenge because of complications, including nonunion, malunion, and the potential for an open injury. Intramedullary fixation of these fractures has long been the standard of care, allowing for early mobilization, shorter time to weight-bearing, and high union rates.^2-4

The classic infrapatellar approach to intramedullary nailing involves placing the knee in hyperflexion over a bump or radiolucent triangle and inserting the nail through a longitudinal incision in line with the fibers of the patellar tendon. Deforming muscle forces often cause proximal-third tibial fractures and segmental fractures to fall into valgus and procurvatum. To counter these deforming forces, orthopedic surgeons have used some novel surgical approaches, including use of blocking screws⁵ and a parapatellar approach that could be used with the knee in semi-extended position.⁶ Anterior knee pain has been reported as a common complication of tibial nailing (reported incidence, 56%).⁷ In a prospective randomized controlled study, Toivanen and colleagues⁸ found no difference in incidence of knee pain between patellar tendon splitting and parapatellar approaches.

Techniques have been developed to insert the nail through a semi-extended suprapatellar approach to facilitate intraoperative imaging, allow easier access to starting-site position, and counter deforming forces. Although outcomes of traditional infrapatellar nailing have been well documented, there is a paucity of literature on outcomes of using a suprapatellar approach. Splitting the quadriceps tendon causes scar tissue to form superior to the patella versus the anterior knee, which may reduce flexion-related pain or kneeling pain.⁹ The infrapatellar nerve is also well protected with this approach.

We conducted a study to determine differences in functional knee pain in patients who underwent either traditional infrapatellar nailing or suprapatellar nailing. We hypothesized that there would be no difference in functional knee scores between these approaches and that, when compared with the infrapatellar approach, the suprapatellar approach would result in improved postoperative reduction and reduced intraoperative fluoroscopy time.

Materials and Methods

This study was approved by our institutional review board. We searched our level I trauma center’s database for Current Procedural Terminology (CPT) code 27759 to identify all patients who had a tibial shaft fracture fixed with an intramedullary implant between January 2009 and February 2013. Radiographs, operative reports, and inpatient records were reviewed. Patients older than 18 years at time of injury and patients with an isolated tibial shaft fracture (Orthopaedic Trauma Association type 42 A-C) surgically fixed with an intramedullary nail through either a traditional infrapatellar approach or a suprapatellar approach were included in the study. Exclusion criteria were required fasciotomy, Gustilo type 3B or 3C open fracture, prior knee surgery, additional orthopedic injury, and preexisting radiographic evidence of degenerative joint disease.

In addition to surgical approach, demographic data, including body mass index (BMI), age, sex, and mechanism of injury, were documented from the medical record. Each patient was contacted by telephone by an investigator blinded to surgical exposure, and the 12-item Oxford Knee Score (OKS) questionnaire was administered (Figure). Operative time, quality of reduction on postoperative radiographs, and intraoperative fluoroscopy time were compared between the 2 approaches. We determined quality of reduction by measuring the angle between the line perpendicular to the tibial plateau and plafond on both the anteroposterior and lateral postoperative radiographs. Rotation was determined by measuring displacement of the fracture by cortical widths. The infrapatellar and suprapatellar groups were statistically analyzed with an unpaired, 2-tailed Student t test. Categorical variables between groups were analyzed with the χ² test or, when expected values in a cell were less than 5, the Fisher exact test.

We then conducted an a priori power analysis to determine the appropriate sample size. To detect the reported minimally clinically important difference in the OKS of 5.2,¹⁰ estimating an approximate 20% larger patient population in the infrapatellar group, we would need to enroll 24 infrapatellar patients and 20 suprapatellar patients to achieve a power of 0.80 with a type I error rate of 0.05.¹¹ This analysis is also based on an estimated OKS standard deviation of 6, which has been reported in several studies.^12,13

Results

We identified 176 patients who had the CPT code for intramedullary fixation of a tibial shaft fracture between January 2009 and February 2013. After analysis of radiographs and medical records, 82 patients met the inclusion criteria. Thirty-six (45%) of the original 82 patients were lost to follow-up after attempts to contact them by telephone. One patient refused to participate in the study. Twenty-four patients underwent traditional infrapatellar nailing, and 21 patients had a suprapatellar nail placed with approach-specific instrumentation. Nine patients had an open fracture. There was no significant difference between the groups in terms of sex, age, BMI, mechanism of injury, or operative time (Table 1). There was also no difference (P = .210) in fracture location between groups (0 proximal-third, 14 midshaft, 10 distal-third vs 3 proximal-third, 10 midshaft, 8 distal-third). Mean age was 37.6 years (range, 20-65 years) for the infrapatellar group and 38.5 years (range, 18-68 years) for the suprapatellar group (P = .839). Mean follow-up was significantly (P < .001) shorter for the suprapatellar group (12 mo; range, 3-33 mo) than for the infrapatellar group (25 mo; range, 4-43 mo).

Mean OKS (maximum, 48 points) was 40.1 (range, 11-48) for the infrapatellar group and 36.7 (range, 2-48) for the suprapatellar group (P = .293). Table 2 summarizes the data. Radiographic reduction in the sagittal plane was improved (P = .044) in the suprapatellar group (2.90°) compared with the infrapatellar group (4.58°). There was no difference in rotational malreduction (0.31 vs 0.25 cortical width; P = .599) or in reduction in the coronal plane (2.52° vs 3.17°; P = .280). All patients in both groups maintained radiographic reduction within 5° in any plane throughout follow-up. There was no difference (P = .654) in radiographic follow-up between the infrapatellar group (11 mo) and the suprapatellar group (12 mo). The 1 nonunion in the suprapatellar group required return to the operating room for exchange intramedullary nailing. The suprapatellar approach required less (P = .003) operative fluoroscopy time (80.8 s; range, 46-180 s) than the standard infrapatellar approach (122.1 s; range, 71-240 s). Two patients in the suprapatellar group and 8 in the infrapatellar group did not have their fluoroscopy time recorded in the operative report.

Discussion

We have described the first retrospective cohort-comparison study of functional knee scores associated with traditional infrapatellar nailing and suprapatellar nailing. Although much has been written about the incidence of anterior knee pain with use of a patellar splitting or parapatellar approach, the clinical effects of knee pain after use of suprapatellar nails are yet to be addressed. In a cadaveric study, Gelbke and colleagues¹⁴ found higher mean patellofemoral pressures and higher peak contact pressures with a suprapatellar approach. These numbers, however, were still far below the threshold for chondrocyte damage, and that study is yet to be clinically validated. Our data showed no difference in OKS between the 2 groups. Despite being intra-articular, approach-specific instrumentation may protect the trochlea and patellar cartilage.

Although the OKS questionnaire was originally developed and widely validated to describe clinical outcomes of total knee arthroplasty,^15,16 it has also been evaluated for other interventions, including viscosupplementation injections¹⁷ and high tibial osteotomy.¹⁸ We used the OKS questionnaire in our study because it is simple to administer by telephone and is not as cumbersome as the Knee Society Score or the Western Ontario and McMaster Universities Osteoarthritis Index. It is also more specific to the knee than generalized outcome measures used in trauma, such as the Short Form 36 (SF-36). Sanders and colleagues¹⁹ reported excellent tibial alignment, radiographic union, and knee range of motion using semi-extended tibial nailing with a suprapatellar approach. For outcome measures, they used the Lysholm Knee Score and the SF-36. Our clinical and radiographic results confirmed their finding—that the semi-extended suprapatellar approach is an option for tibial nailing.

OKS results by question (Table 3) showed that the infrapatellar group had less pain walking down stairs. This result approached statistical significance (P = .063). As surgeons at our institution began using the suprapatellar approach only during the final 2 years of the study period, mean follow-up was significantly (P < .001) less than for the infrapatellar group (12 vs 25 mo). Although there was no statistically significant difference in reduction quality on anteroposterior radiographs, the suprapatellar approach had improved (P = .044) reduction on lateral radiographs (2.90° vs 4.58°).

Although operative time did not differ between our 2 groups, significantly (P = .003) less fluoroscopy time was required for suprapatellar nails (80.8 s) than for infrapatellar nails (122.1 s). Positioning the knee in the semi-extended position offers easier access for fluoroscopy and less radiation exposure for the patient. Placing the nail in extension also helps eliminate the deforming forces that cause malreduction of proximal tibial shaft or segmental fractures. However, our study was limited in that only 2 surgeons at our institution used the suprapatellar approach, and both were fellowship-trained in orthopedic traumatology. This situation could have introduced bias into the interpretation of fluoroscopy data, as these surgeons may have been more comfortable with the procedure and less likely to use fluoroscopy. Both surgeons also performed infrapatellar nailing during the study period, and there was no statistical difference in fracture patterns between the groups, thus minimizing bias.

This study was retrospective but had several strengths. Sample size met the prestudy power analysis to determine a minimally clinically important difference in OKS results. The investigator who administered the telephone survey was blinded to surgical approach. This study was also the first clinical study to compare outcomes of infrapatellar and suprapatellar nailing. However, the study’s follow-up rate was a weakness. The patient population at our academic, urban, level I trauma center is transient. We lost 36 patients (45%) to follow-up; their telephone numbers in the hospital records likely changed since surgery, and we could not contact these patients.

Conclusion

Our retrospective cohort study found no difference in OKS between traditional infrapatellar nailing and suprapatellar nailing for diaphyseal tibia fractures. Suprapatellar nails require less fluoroscopy time and may show improved radiographic reduction in the sagittal plane. Although further study is needed, the suprapatellar entry portal appears to be a safe alternative for tibial nailing with use of appropriate instrumentation.

With an incidence of 75,000 per year in the United States alone, fractures of the tibial shaft are among the most common long-bone fractures.¹ Diaphyseal tibial fractures present a unique treatment challenge because of complications, including nonunion, malunion, and the potential for an open injury. Intramedullary fixation of these fractures has long been the standard of care, allowing for early mobilization, shorter time to weight-bearing, and high union rates.^2-4

The classic infrapatellar approach to intramedullary nailing involves placing the knee in hyperflexion over a bump or radiolucent triangle and inserting the nail through a longitudinal incision in line with the fibers of the patellar tendon. Deforming muscle forces often cause proximal-third tibial fractures and segmental fractures to fall into valgus and procurvatum. To counter these deforming forces, orthopedic surgeons have used some novel surgical approaches, including use of blocking screws⁵ and a parapatellar approach that could be used with the knee in semi-extended position.⁶ Anterior knee pain has been reported as a common complication of tibial nailing (reported incidence, 56%).⁷ In a prospective randomized controlled study, Toivanen and colleagues⁸ found no difference in incidence of knee pain between patellar tendon splitting and parapatellar approaches.

Techniques have been developed to insert the nail through a semi-extended suprapatellar approach to facilitate intraoperative imaging, allow easier access to starting-site position, and counter deforming forces. Although outcomes of traditional infrapatellar nailing have been well documented, there is a paucity of literature on outcomes of using a suprapatellar approach. Splitting the quadriceps tendon causes scar tissue to form superior to the patella versus the anterior knee, which may reduce flexion-related pain or kneeling pain.⁹ The infrapatellar nerve is also well protected with this approach.

We conducted a study to determine differences in functional knee pain in patients who underwent either traditional infrapatellar nailing or suprapatellar nailing. We hypothesized that there would be no difference in functional knee scores between these approaches and that, when compared with the infrapatellar approach, the suprapatellar approach would result in improved postoperative reduction and reduced intraoperative fluoroscopy time.

Materials and Methods

This study was approved by our institutional review board. We searched our level I trauma center’s database for Current Procedural Terminology (CPT) code 27759 to identify all patients who had a tibial shaft fracture fixed with an intramedullary implant between January 2009 and February 2013. Radiographs, operative reports, and inpatient records were reviewed. Patients older than 18 years at time of injury and patients with an isolated tibial shaft fracture (Orthopaedic Trauma Association type 42 A-C) surgically fixed with an intramedullary nail through either a traditional infrapatellar approach or a suprapatellar approach were included in the study. Exclusion criteria were required fasciotomy, Gustilo type 3B or 3C open fracture, prior knee surgery, additional orthopedic injury, and preexisting radiographic evidence of degenerative joint disease.

In addition to surgical approach, demographic data, including body mass index (BMI), age, sex, and mechanism of injury, were documented from the medical record. Each patient was contacted by telephone by an investigator blinded to surgical exposure, and the 12-item Oxford Knee Score (OKS) questionnaire was administered (Figure). Operative time, quality of reduction on postoperative radiographs, and intraoperative fluoroscopy time were compared between the 2 approaches. We determined quality of reduction by measuring the angle between the line perpendicular to the tibial plateau and plafond on both the anteroposterior and lateral postoperative radiographs. Rotation was determined by measuring displacement of the fracture by cortical widths. The infrapatellar and suprapatellar groups were statistically analyzed with an unpaired, 2-tailed Student t test. Categorical variables between groups were analyzed with the χ² test or, when expected values in a cell were less than 5, the Fisher exact test.

We then conducted an a priori power analysis to determine the appropriate sample size. To detect the reported minimally clinically important difference in the OKS of 5.2,¹⁰ estimating an approximate 20% larger patient population in the infrapatellar group, we would need to enroll 24 infrapatellar patients and 20 suprapatellar patients to achieve a power of 0.80 with a type I error rate of 0.05.¹¹ This analysis is also based on an estimated OKS standard deviation of 6, which has been reported in several studies.^12,13

Results

We identified 176 patients who had the CPT code for intramedullary fixation of a tibial shaft fracture between January 2009 and February 2013. After analysis of radiographs and medical records, 82 patients met the inclusion criteria. Thirty-six (45%) of the original 82 patients were lost to follow-up after attempts to contact them by telephone. One patient refused to participate in the study. Twenty-four patients underwent traditional infrapatellar nailing, and 21 patients had a suprapatellar nail placed with approach-specific instrumentation. Nine patients had an open fracture. There was no significant difference between the groups in terms of sex, age, BMI, mechanism of injury, or operative time (Table 1). There was also no difference (P = .210) in fracture location between groups (0 proximal-third, 14 midshaft, 10 distal-third vs 3 proximal-third, 10 midshaft, 8 distal-third). Mean age was 37.6 years (range, 20-65 years) for the infrapatellar group and 38.5 years (range, 18-68 years) for the suprapatellar group (P = .839). Mean follow-up was significantly (P < .001) shorter for the suprapatellar group (12 mo; range, 3-33 mo) than for the infrapatellar group (25 mo; range, 4-43 mo).

Mean OKS (maximum, 48 points) was 40.1 (range, 11-48) for the infrapatellar group and 36.7 (range, 2-48) for the suprapatellar group (P = .293). Table 2 summarizes the data. Radiographic reduction in the sagittal plane was improved (P = .044) in the suprapatellar group (2.90°) compared with the infrapatellar group (4.58°). There was no difference in rotational malreduction (0.31 vs 0.25 cortical width; P = .599) or in reduction in the coronal plane (2.52° vs 3.17°; P = .280). All patients in both groups maintained radiographic reduction within 5° in any plane throughout follow-up. There was no difference (P = .654) in radiographic follow-up between the infrapatellar group (11 mo) and the suprapatellar group (12 mo). The 1 nonunion in the suprapatellar group required return to the operating room for exchange intramedullary nailing. The suprapatellar approach required less (P = .003) operative fluoroscopy time (80.8 s; range, 46-180 s) than the standard infrapatellar approach (122.1 s; range, 71-240 s). Two patients in the suprapatellar group and 8 in the infrapatellar group did not have their fluoroscopy time recorded in the operative report.

Discussion

We have described the first retrospective cohort-comparison study of functional knee scores associated with traditional infrapatellar nailing and suprapatellar nailing. Although much has been written about the incidence of anterior knee pain with use of a patellar splitting or parapatellar approach, the clinical effects of knee pain after use of suprapatellar nails are yet to be addressed. In a cadaveric study, Gelbke and colleagues¹⁴ found higher mean patellofemoral pressures and higher peak contact pressures with a suprapatellar approach. These numbers, however, were still far below the threshold for chondrocyte damage, and that study is yet to be clinically validated. Our data showed no difference in OKS between the 2 groups. Despite being intra-articular, approach-specific instrumentation may protect the trochlea and patellar cartilage.

Although the OKS questionnaire was originally developed and widely validated to describe clinical outcomes of total knee arthroplasty,^15,16 it has also been evaluated for other interventions, including viscosupplementation injections¹⁷ and high tibial osteotomy.¹⁸ We used the OKS questionnaire in our study because it is simple to administer by telephone and is not as cumbersome as the Knee Society Score or the Western Ontario and McMaster Universities Osteoarthritis Index. It is also more specific to the knee than generalized outcome measures used in trauma, such as the Short Form 36 (SF-36). Sanders and colleagues¹⁹ reported excellent tibial alignment, radiographic union, and knee range of motion using semi-extended tibial nailing with a suprapatellar approach. For outcome measures, they used the Lysholm Knee Score and the SF-36. Our clinical and radiographic results confirmed their finding—that the semi-extended suprapatellar approach is an option for tibial nailing.

OKS results by question (Table 3) showed that the infrapatellar group had less pain walking down stairs. This result approached statistical significance (P = .063). As surgeons at our institution began using the suprapatellar approach only during the final 2 years of the study period, mean follow-up was significantly (P < .001) less than for the infrapatellar group (12 vs 25 mo). Although there was no statistically significant difference in reduction quality on anteroposterior radiographs, the suprapatellar approach had improved (P = .044) reduction on lateral radiographs (2.90° vs 4.58°).

Although operative time did not differ between our 2 groups, significantly (P = .003) less fluoroscopy time was required for suprapatellar nails (80.8 s) than for infrapatellar nails (122.1 s). Positioning the knee in the semi-extended position offers easier access for fluoroscopy and less radiation exposure for the patient. Placing the nail in extension also helps eliminate the deforming forces that cause malreduction of proximal tibial shaft or segmental fractures. However, our study was limited in that only 2 surgeons at our institution used the suprapatellar approach, and both were fellowship-trained in orthopedic traumatology. This situation could have introduced bias into the interpretation of fluoroscopy data, as these surgeons may have been more comfortable with the procedure and less likely to use fluoroscopy. Both surgeons also performed infrapatellar nailing during the study period, and there was no statistical difference in fracture patterns between the groups, thus minimizing bias.

This study was retrospective but had several strengths. Sample size met the prestudy power analysis to determine a minimally clinically important difference in OKS results. The investigator who administered the telephone survey was blinded to surgical approach. This study was also the first clinical study to compare outcomes of infrapatellar and suprapatellar nailing. However, the study’s follow-up rate was a weakness. The patient population at our academic, urban, level I trauma center is transient. We lost 36 patients (45%) to follow-up; their telephone numbers in the hospital records likely changed since surgery, and we could not contact these patients.

Conclusion

Our retrospective cohort study found no difference in OKS between traditional infrapatellar nailing and suprapatellar nailing for diaphyseal tibia fractures. Suprapatellar nails require less fluoroscopy time and may show improved radiographic reduction in the sagittal plane. Although further study is needed, the suprapatellar entry portal appears to be a safe alternative for tibial nailing with use of appropriate instrumentation.

With an incidence of 75,000 per year in the United States alone, fractures of the tibial shaft are among the most common long-bone fractures.¹ Diaphyseal tibial fractures present a unique treatment challenge because of complications, including nonunion, malunion, and the potential for an open injury. Intramedullary fixation of these fractures has long been the standard of care, allowing for early mobilization, shorter time to weight-bearing, and high union rates.^2-4

The classic infrapatellar approach to intramedullary nailing involves placing the knee in hyperflexion over a bump or radiolucent triangle and inserting the nail through a longitudinal incision in line with the fibers of the patellar tendon. Deforming muscle forces often cause proximal-third tibial fractures and segmental fractures to fall into valgus and procurvatum. To counter these deforming forces, orthopedic surgeons have used some novel surgical approaches, including use of blocking screws⁵ and a parapatellar approach that could be used with the knee in semi-extended position.⁶ Anterior knee pain has been reported as a common complication of tibial nailing (reported incidence, 56%).⁷ In a prospective randomized controlled study, Toivanen and colleagues⁸ found no difference in incidence of knee pain between patellar tendon splitting and parapatellar approaches.

Techniques have been developed to insert the nail through a semi-extended suprapatellar approach to facilitate intraoperative imaging, allow easier access to starting-site position, and counter deforming forces. Although outcomes of traditional infrapatellar nailing have been well documented, there is a paucity of literature on outcomes of using a suprapatellar approach. Splitting the quadriceps tendon causes scar tissue to form superior to the patella versus the anterior knee, which may reduce flexion-related pain or kneeling pain.⁹ The infrapatellar nerve is also well protected with this approach.

We conducted a study to determine differences in functional knee pain in patients who underwent either traditional infrapatellar nailing or suprapatellar nailing. We hypothesized that there would be no difference in functional knee scores between these approaches and that, when compared with the infrapatellar approach, the suprapatellar approach would result in improved postoperative reduction and reduced intraoperative fluoroscopy time.

Materials and Methods

This study was approved by our institutional review board. We searched our level I trauma center’s database for Current Procedural Terminology (CPT) code 27759 to identify all patients who had a tibial shaft fracture fixed with an intramedullary implant between January 2009 and February 2013. Radiographs, operative reports, and inpatient records were reviewed. Patients older than 18 years at time of injury and patients with an isolated tibial shaft fracture (Orthopaedic Trauma Association type 42 A-C) surgically fixed with an intramedullary nail through either a traditional infrapatellar approach or a suprapatellar approach were included in the study. Exclusion criteria were required fasciotomy, Gustilo type 3B or 3C open fracture, prior knee surgery, additional orthopedic injury, and preexisting radiographic evidence of degenerative joint disease.

In addition to surgical approach, demographic data, including body mass index (BMI), age, sex, and mechanism of injury, were documented from the medical record. Each patient was contacted by telephone by an investigator blinded to surgical exposure, and the 12-item Oxford Knee Score (OKS) questionnaire was administered (Figure). Operative time, quality of reduction on postoperative radiographs, and intraoperative fluoroscopy time were compared between the 2 approaches. We determined quality of reduction by measuring the angle between the line perpendicular to the tibial plateau and plafond on both the anteroposterior and lateral postoperative radiographs. Rotation was determined by measuring displacement of the fracture by cortical widths. The infrapatellar and suprapatellar groups were statistically analyzed with an unpaired, 2-tailed Student t test. Categorical variables between groups were analyzed with the χ² test or, when expected values in a cell were less than 5, the Fisher exact test.

We then conducted an a priori power analysis to determine the appropriate sample size. To detect the reported minimally clinically important difference in the OKS of 5.2,¹⁰ estimating an approximate 20% larger patient population in the infrapatellar group, we would need to enroll 24 infrapatellar patients and 20 suprapatellar patients to achieve a power of 0.80 with a type I error rate of 0.05.¹¹ This analysis is also based on an estimated OKS standard deviation of 6, which has been reported in several studies.^12,13

Results

We identified 176 patients who had the CPT code for intramedullary fixation of a tibial shaft fracture between January 2009 and February 2013. After analysis of radiographs and medical records, 82 patients met the inclusion criteria. Thirty-six (45%) of the original 82 patients were lost to follow-up after attempts to contact them by telephone. One patient refused to participate in the study. Twenty-four patients underwent traditional infrapatellar nailing, and 21 patients had a suprapatellar nail placed with approach-specific instrumentation. Nine patients had an open fracture. There was no significant difference between the groups in terms of sex, age, BMI, mechanism of injury, or operative time (Table 1). There was also no difference (P = .210) in fracture location between groups (0 proximal-third, 14 midshaft, 10 distal-third vs 3 proximal-third, 10 midshaft, 8 distal-third). Mean age was 37.6 years (range, 20-65 years) for the infrapatellar group and 38.5 years (range, 18-68 years) for the suprapatellar group (P = .839). Mean follow-up was significantly (P < .001) shorter for the suprapatellar group (12 mo; range, 3-33 mo) than for the infrapatellar group (25 mo; range, 4-43 mo).

Mean OKS (maximum, 48 points) was 40.1 (range, 11-48) for the infrapatellar group and 36.7 (range, 2-48) for the suprapatellar group (P = .293). Table 2 summarizes the data. Radiographic reduction in the sagittal plane was improved (P = .044) in the suprapatellar group (2.90°) compared with the infrapatellar group (4.58°). There was no difference in rotational malreduction (0.31 vs 0.25 cortical width; P = .599) or in reduction in the coronal plane (2.52° vs 3.17°; P = .280). All patients in both groups maintained radiographic reduction within 5° in any plane throughout follow-up. There was no difference (P = .654) in radiographic follow-up between the infrapatellar group (11 mo) and the suprapatellar group (12 mo). The 1 nonunion in the suprapatellar group required return to the operating room for exchange intramedullary nailing. The suprapatellar approach required less (P = .003) operative fluoroscopy time (80.8 s; range, 46-180 s) than the standard infrapatellar approach (122.1 s; range, 71-240 s). Two patients in the suprapatellar group and 8 in the infrapatellar group did not have their fluoroscopy time recorded in the operative report.

Discussion

We have described the first retrospective cohort-comparison study of functional knee scores associated with traditional infrapatellar nailing and suprapatellar nailing. Although much has been written about the incidence of anterior knee pain with use of a patellar splitting or parapatellar approach, the clinical effects of knee pain after use of suprapatellar nails are yet to be addressed. In a cadaveric study, Gelbke and colleagues¹⁴ found higher mean patellofemoral pressures and higher peak contact pressures with a suprapatellar approach. These numbers, however, were still far below the threshold for chondrocyte damage, and that study is yet to be clinically validated. Our data showed no difference in OKS between the 2 groups. Despite being intra-articular, approach-specific instrumentation may protect the trochlea and patellar cartilage.

Although the OKS questionnaire was originally developed and widely validated to describe clinical outcomes of total knee arthroplasty,^15,16 it has also been evaluated for other interventions, including viscosupplementation injections¹⁷ and high tibial osteotomy.¹⁸ We used the OKS questionnaire in our study because it is simple to administer by telephone and is not as cumbersome as the Knee Society Score or the Western Ontario and McMaster Universities Osteoarthritis Index. It is also more specific to the knee than generalized outcome measures used in trauma, such as the Short Form 36 (SF-36). Sanders and colleagues¹⁹ reported excellent tibial alignment, radiographic union, and knee range of motion using semi-extended tibial nailing with a suprapatellar approach. For outcome measures, they used the Lysholm Knee Score and the SF-36. Our clinical and radiographic results confirmed their finding—that the semi-extended suprapatellar approach is an option for tibial nailing.

OKS results by question (Table 3) showed that the infrapatellar group had less pain walking down stairs. This result approached statistical significance (P = .063). As surgeons at our institution began using the suprapatellar approach only during the final 2 years of the study period, mean follow-up was significantly (P < .001) less than for the infrapatellar group (12 vs 25 mo). Although there was no statistically significant difference in reduction quality on anteroposterior radiographs, the suprapatellar approach had improved (P = .044) reduction on lateral radiographs (2.90° vs 4.58°).

Although operative time did not differ between our 2 groups, significantly (P = .003) less fluoroscopy time was required for suprapatellar nails (80.8 s) than for infrapatellar nails (122.1 s). Positioning the knee in the semi-extended position offers easier access for fluoroscopy and less radiation exposure for the patient. Placing the nail in extension also helps eliminate the deforming forces that cause malreduction of proximal tibial shaft or segmental fractures. However, our study was limited in that only 2 surgeons at our institution used the suprapatellar approach, and both were fellowship-trained in orthopedic traumatology. This situation could have introduced bias into the interpretation of fluoroscopy data, as these surgeons may have been more comfortable with the procedure and less likely to use fluoroscopy. Both surgeons also performed infrapatellar nailing during the study period, and there was no statistical difference in fracture patterns between the groups, thus minimizing bias.

This study was retrospective but had several strengths. Sample size met the prestudy power analysis to determine a minimally clinically important difference in OKS results. The investigator who administered the telephone survey was blinded to surgical approach. This study was also the first clinical study to compare outcomes of infrapatellar and suprapatellar nailing. However, the study’s follow-up rate was a weakness. The patient population at our academic, urban, level I trauma center is transient. We lost 36 patients (45%) to follow-up; their telephone numbers in the hospital records likely changed since surgery, and we could not contact these patients.

Conclusion

Our retrospective cohort study found no difference in OKS between traditional infrapatellar nailing and suprapatellar nailing for diaphyseal tibia fractures. Suprapatellar nails require less fluoroscopy time and may show improved radiographic reduction in the sagittal plane. Although further study is needed, the suprapatellar entry portal appears to be a safe alternative for tibial nailing with use of appropriate instrumentation.

The use of androgen deprivation therapy (ADT) for treatment of prostate cancer was associated with increased risk of Alzheimer’s disease, and patients with greater duration of ADT use had higher risks, according to medical records data analysis.

ADT use was significantly associated with Alzheimer’s disease risk, with a hazard ratio (HR) of 1.88 by propensity score–matched Cox regression analysis (95% confidence interval, 1.10-3.20; P = .021), and HR of 1.66 by traditional multivariable-adjusted Cox regression analysis (95% CI, 1.05-2.64; P = .031).

Patients who used ADT for 12 months or more had the greatest risk observed (HR, 2.12; 95% CI, 1.11-4.03; P = .011), and the risk increased by category of ADT duration (P for trend = .016).

Investigators used a novel text-processing pipeline to analyze clinical data, extracting disease and terminology codes, medication lists, and positive-present mentions of drug and disease concepts from clinical notes.

“Use of the electronic medical record in this way allows rapid investigation of a rich data source to study a broad range of postmarketing outcome, including those unlikely to be seen in smaller clinical trials,” wrote Dr. Kevin T. Nead of the University of Pennsylvania, Philadelphia, and his colleagues (J Clin Oncol. 2015 Dec 7. doi: 10.1200/JCO.2015.63.6266).

The study evaluated 16,888 patients with prostate cancer; in total, 2,397 received ADT and 125 were diagnosed with Alzheimer’s disease during a median follow-up of 2.7 years. The median time to Alzheimer’s disease diagnosis was 4 years.

The analysis replicated previously known associations between Alzheimer’s disease and age (HR, 1.06; P less than .001) and cardiovascular disease (HR, 1.60; P = .031), supporting the validity of the method, according to the researchers.

The use of androgen deprivation therapy (ADT) for treatment of prostate cancer was associated with increased risk of Alzheimer’s disease, and patients with greater duration of ADT use had higher risks, according to medical records data analysis.

ADT use was significantly associated with Alzheimer’s disease risk, with a hazard ratio (HR) of 1.88 by propensity score–matched Cox regression analysis (95% confidence interval, 1.10-3.20; P = .021), and HR of 1.66 by traditional multivariable-adjusted Cox regression analysis (95% CI, 1.05-2.64; P = .031).

Patients who used ADT for 12 months or more had the greatest risk observed (HR, 2.12; 95% CI, 1.11-4.03; P = .011), and the risk increased by category of ADT duration (P for trend = .016).

Investigators used a novel text-processing pipeline to analyze clinical data, extracting disease and terminology codes, medication lists, and positive-present mentions of drug and disease concepts from clinical notes.

“Use of the electronic medical record in this way allows rapid investigation of a rich data source to study a broad range of postmarketing outcome, including those unlikely to be seen in smaller clinical trials,” wrote Dr. Kevin T. Nead of the University of Pennsylvania, Philadelphia, and his colleagues (J Clin Oncol. 2015 Dec 7. doi: 10.1200/JCO.2015.63.6266).

The study evaluated 16,888 patients with prostate cancer; in total, 2,397 received ADT and 125 were diagnosed with Alzheimer’s disease during a median follow-up of 2.7 years. The median time to Alzheimer’s disease diagnosis was 4 years.

The analysis replicated previously known associations between Alzheimer’s disease and age (HR, 1.06; P less than .001) and cardiovascular disease (HR, 1.60; P = .031), supporting the validity of the method, according to the researchers.

The use of androgen deprivation therapy (ADT) for treatment of prostate cancer was associated with increased risk of Alzheimer’s disease, and patients with greater duration of ADT use had higher risks, according to medical records data analysis.

ADT use was significantly associated with Alzheimer’s disease risk, with a hazard ratio (HR) of 1.88 by propensity score–matched Cox regression analysis (95% confidence interval, 1.10-3.20; P = .021), and HR of 1.66 by traditional multivariable-adjusted Cox regression analysis (95% CI, 1.05-2.64; P = .031).

Patients who used ADT for 12 months or more had the greatest risk observed (HR, 2.12; 95% CI, 1.11-4.03; P = .011), and the risk increased by category of ADT duration (P for trend = .016).

Investigators used a novel text-processing pipeline to analyze clinical data, extracting disease and terminology codes, medication lists, and positive-present mentions of drug and disease concepts from clinical notes.

“Use of the electronic medical record in this way allows rapid investigation of a rich data source to study a broad range of postmarketing outcome, including those unlikely to be seen in smaller clinical trials,” wrote Dr. Kevin T. Nead of the University of Pennsylvania, Philadelphia, and his colleagues (J Clin Oncol. 2015 Dec 7. doi: 10.1200/JCO.2015.63.6266).

The study evaluated 16,888 patients with prostate cancer; in total, 2,397 received ADT and 125 were diagnosed with Alzheimer’s disease during a median follow-up of 2.7 years. The median time to Alzheimer’s disease diagnosis was 4 years.

The analysis replicated previously known associations between Alzheimer’s disease and age (HR, 1.06; P less than .001) and cardiovascular disease (HR, 1.60; P = .031), supporting the validity of the method, according to the researchers.

First described by Runge¹ in 1873 and later termed lawn-tennis arm by Major² in 1883, lateral epicondylitis is a common cause of elbow pain, affecting 1% to 3% of the general population each year.^3,4 Given that prevalence estimates are up to 15% among workers in repetitive hand task industries,^5-7 symptoms of lateral epicondylitis are thought to be related to recurring wrist extension and alternating forearm pronation and supination.⁸ Between 80% and 90% of patients with lateral epicondylitis experience symptomatic improvement with conservative therapy,^9-11 including rest and use of nonsteroidal anti-inflammatory medications,¹² physical therapy,^13,14 corticosteroid injections,^10,15,16 orthoses,^17,18 and shock wave therapy.¹⁹ However, between 4% and 11% of patients with newly diagnosed lateral epicondylitis do not respond to prolonged (6- to 12-month) conservative treatment and then require operative intervention,^11,20,21 with some referral practices reporting rates as high as 25%.²²

Traditionally, operative management of lateral epicondylitis involved open débridement of the extensor carpi radialis brevis (ECRB).^11,20 More recently, the spectrum of operations for lateral epicondylitis has expanded to include procedures that repair the extensor origin after débridement of the torn tendon and angiofibroblastic dysplasia; procedures that use fasciotomy or direct release of the extensor origin from the epicondyle to relieve tension on the common extensor; procedures directed at the radial or posterior interosseous nerve; and procedures that use arthroscopic techniques to divide the orbicular ligament, reshape the radial head, or release the extensor origin.²³ There has been debate about the value of repairing the ECRB, lengthening the ECRB, simultaneously decompressing the radial nerve or resecting epicondylar bone, and performing the procedures percutaneously, endoscopically, or arthroscopically.^24-28 Despite multiple studies of the outcomes of these procedures,^11,29-31 little is known regarding US national trends for operative treatment of lateral epicondylitis. Understanding national practice patterns and disease burden is essential to allocation of limited health care resources.

We conducted a study to determine US national trends in use of ambulatory surgery for lateral epicondylitis. We focused on age, sex, surgical setting, anesthetic type, and payment method.

Methods

As the National Survey of Ambulatory Surgery³² (NSAS) is an administrative dataset in which all data are deidentified and available for public use, this study was exempt from requiring institutional review board approval.

NSAS data were used to analyze trends in treatment of lateral epicondylitis between 1994 and 2006. NSAS was undertaken by the National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention (CDC) to obtain information about the use of ambulatory surgery in the United States. Since the early 1980s, ambulatory surgery has increased in the United States because of advances in medical technology and cost-containment initiatives.³³ The number of procedures being performed in ambulatory surgery centers increased from 31.5 million in 1996 to 53.3 million in 2006.³⁴ Funded by the CDC, NSAS is a national study that involves both hospital-based and freestanding ambulatory surgery centers and provides the most recent and comprehensive overview of ambulatory surgery in the United States.³⁵ Because of budgetary limitations, 2006 was the last year in which data for NSAS were collected. Data for NSAS come from Medicare-participating, noninstitutional hospitals (excluding military hospitals, federal facilities, and Veteran Affairs hospitals) in all 50 states and the District of Columbia with a minimum of 6 beds staffed for patient use. NSAS used only short-stay hospitals (hospitals with an average length of stay for all patients of less than 30 days) or hospitals that had a specialty of general (medical or surgical) or children’s general. NSAS was conducted in 1994, 1996, and 2006 with medical information recorded on patient abstracts coded by contract staff. NSAS selected a sample of ambulatory surgery visits using a systematic random sampling procedure, and selection of visits within each facility was done separately for each location where ambulatory surgery was performed. In 1994, 751 facilities were sampled, and 88% of hospitals responded. In 1996, 750 facilities were sampled, and 91% of hospitals responded. In 2006, 696 facilities were sampled, and 75% responded. The surveys used International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes³⁶ to classify medical diagnoses and procedures. To produce an unbiased national estimate, NCHS used multistage estimate procedures, including inflation by reciprocals of the probabilities of sample selection, population-weighting ratio adjustments, and adjustment for no response.³⁷

Demographic and medical information was obtained for people with an ICD-9-CM diagnosis code of lateral epicondylitis (726.32), using previously described techniques.³⁸ Data were then recorded for age, sex, facility type, insurance type, anesthesia type, diagnoses, and procedures.

Descriptive statistics consisted of means and standard deviations for continuous variables and frequency and percentages for discrete variables. Because NSAS data were collected on the basis of a probabilistic sample scheme, they were analyzed using a sampling weighting method. Sampling weights (inverse of selection probability) provided by the CDC were used to account for unequal sampling probabilities and to produce estimates for all visits in the United States. A Taylor linearization model provided by the CDC estimates was used to calculate standard error and confidence intervals (CIs) of the data. Standard error is a measure of sampling variability that occurs by chance because only a sample rather than the entire universe is surveyed. To define population parameters, NCHS chose 95% CIs along with a point estimate. Direct statistical comparison between years cannot be performed because of sampling differences in the database compared between years. The CIs, however, can suggest statistical differences if the data are nonoverlapping. US census data were used to obtain national population estimates for each year of the study (1994, 1996, 2006).³⁹ Rates were presented as number of procedures per 100,000 standard population. For age, a direct adjustment procedure was used, and the US population in 2000 was selected as the standard population. Applying sex-specific rates to the standard population and dividing by the total in the standard population, we calculated sex-adjusted rates for each year. All data were analyzed using SPSS Version 20 software.

Results

A total of 30,311 ambulatory surgical procedures (95% CI, 27,292-33,330) or 10.44 per 100,000 capita were recorded by NSAS for the treatment of lateral epicondylitis in 2006 (Table 1). This represents a large increase in the total number of ambulatory procedures, from 21,852 in 1994 (95% CI, 19,981-23,722; 7.29/100,000) and 20,372 in 1996 (95% CI, 18,660-22,083; 6.73/100,000).

Between 1994 and 2006, the sex-adjusted rate of ambulatory surgery for lateral epicondylitis increased by 85% among females (7.74/100,000 to 14.31/100,000), whereas the rate decreased by 31% among males (8.07/100,000 to 5.59/100,000) (Table 1). The age-adjusted rate of ambulatory surgery for lateral epicondylitis increased among all age groups except the 30–39 years group (Table 2). The largest increase in age-adjusted rates was found for patients older than 50 years (275%) between 1994 and 2006.

During the study period, use of regional anesthesia nearly doubled, from 17% to 30%, whereas use of general anesthesia decreased, from 69% to 57% (Table 3). At all time points, the most common procedure performed for lateral epicondylitis in ambulatory surgery centers was division/release of the joint capsule of the elbow (Table 4). Private insurance remained the most common source of payment for all study years, ranging from 52% to 60% (Table 5). The Figure shows that, between 1994 and 2006, the proportion of surgeries performed in a freestanding ambulatory center increased.

Discussion

In this descriptive epidemiologic study, we used NSAS data to investigate trends in ambulatory surgery for lateral epicondylitis between 1994 and 2006.³² Our results showed that total number of procedures and the population-adjusted rate of procedures for lateral epicondylitis increased during the study period. The largest increase in age-adjusted rates of surgery for lateral epicondylitis was found among patients older than 50 years, whereas the highest age-adjusted rate of ambulatory surgery for lateral epicondylitis was found among patients between ages 40 and 49 years. These findings are similar to those of previous studies, which have shown that most patients with lateral epicondylitis present in the fourth and fifth decades of life.²² Prior reports have suggested that the incidence of lateral epicondylitis in men and women is equal.²² The present study found a change in sex-adjusted rates of ambulatory surgery for lateral epicondylitis between 1994 and 2006. Specifically, in 1994, surgery rates for men and women were similar (8.07/100,000 and 7.74/100,000), but in 2006 the sex-adjusted rate of surgery for lateral epicondylitis was almost 3 times higher for women than for men (14.31/100,000 vs 5.59/100,000).

We also found that the population-adjusted rate of lateral epicondylectomy increased drastically, from 0.4 per 100,000 in 1994 to 3.53 per 100,000 in 2006. Lateral epicondylectomy involves excision of the tip of the lateral epicondyle (typically, 0.5 cm) to produce a cancellous bone surface to which the edges of the débrided extensor tendon can be approximated without tension.²³ It is possible that the increased rate of lateral epicondylectomy reflects evidence-based practice changes during the study period,²⁷ though denervation was found more favorable than epicondylectomy in a recent study by Berry and colleagues.⁴⁰ Future studies should investigate whether rates of epicondylectomy have changed since 2006. In addition, the present study showed a correlation between the introduction of arthroscopic techniques for the treatment of lateral epicondylitis and the period when much research was being conducted on the topic.^24,25,28 As arthroscopic techniques improve, their rates are likely to continue to increase.

Our results also showed an increase in procedures performed in freestanding facilities. The rise in ambulatory surgical volume, speculated to result from more procedures being performed in freestanding facilities,³⁴ has been reported with knee and shoulder arthroscopy.⁴¹ In addition, though general anesthesia remained the most used technique, our results showed a shift toward peripheral nerve blocks. The increase in regional anesthesia, which has also been noted in joint arthroscopy, is thought to stem from the advent of nerve-localizing technology, such as nerve stimulation and ultrasound guidance.⁴¹ Peripheral nerve blocks are favorable on both economic and quality measures, are associated with fewer opioid-related side effects, and overall provide better analgesia in comparison with opioids, highlighting their importance in the ambulatory setting.⁴²

Although large, national databases are well suited to epidemiologic research,⁴³ our study had limitations. As with all databases, NSAS is subject to data entry errors and coding errors.^44,45 However, the database administrators corrected for this by using a multistage estimate procedure with weighting adjustments for no response and population-weighting ratio adjustments.³⁵ Another limitation of this study is its lack of clinical detail, as procedure codes are general and do not allow differentiation between specific patients. Because of the retrospective nature of the analysis and the heterogeneity of the data, assessment of specific surgeries for lateral epicondylitis was limited. Although a strength of using NSAS to perform epidemiologic analyses is its large sample size, this also sacrifices specificity in terms of clinical insight. The results of this study may influence investigations to distinguish differences between procedures used in the treatment of lateral epicondylitis. Furthermore, the results of this study are limited to ambulatory surgery practice patterns in the United States between 1996 and 2006. Last, our ability to perform economic analyses was limited, as data on total hospital cost were not recorded by the surveys.

Conclusion

The increase in ambulatory surgery for lateral epicondylitis, demonstrated in this study, emphasizes the importance of national funding for surveys such as NSAS beyond 2006, as utilization trends may have considerable effects on health care policies that influence the quality of patient care.

First described by Runge¹ in 1873 and later termed lawn-tennis arm by Major² in 1883, lateral epicondylitis is a common cause of elbow pain, affecting 1% to 3% of the general population each year.^3,4 Given that prevalence estimates are up to 15% among workers in repetitive hand task industries,^5-7 symptoms of lateral epicondylitis are thought to be related to recurring wrist extension and alternating forearm pronation and supination.⁸ Between 80% and 90% of patients with lateral epicondylitis experience symptomatic improvement with conservative therapy,^9-11 including rest and use of nonsteroidal anti-inflammatory medications,¹² physical therapy,^13,14 corticosteroid injections,^10,15,16 orthoses,^17,18 and shock wave therapy.¹⁹ However, between 4% and 11% of patients with newly diagnosed lateral epicondylitis do not respond to prolonged (6- to 12-month) conservative treatment and then require operative intervention,^11,20,21 with some referral practices reporting rates as high as 25%.²²

Traditionally, operative management of lateral epicondylitis involved open débridement of the extensor carpi radialis brevis (ECRB).^11,20 More recently, the spectrum of operations for lateral epicondylitis has expanded to include procedures that repair the extensor origin after débridement of the torn tendon and angiofibroblastic dysplasia; procedures that use fasciotomy or direct release of the extensor origin from the epicondyle to relieve tension on the common extensor; procedures directed at the radial or posterior interosseous nerve; and procedures that use arthroscopic techniques to divide the orbicular ligament, reshape the radial head, or release the extensor origin.²³ There has been debate about the value of repairing the ECRB, lengthening the ECRB, simultaneously decompressing the radial nerve or resecting epicondylar bone, and performing the procedures percutaneously, endoscopically, or arthroscopically.^24-28 Despite multiple studies of the outcomes of these procedures,^11,29-31 little is known regarding US national trends for operative treatment of lateral epicondylitis. Understanding national practice patterns and disease burden is essential to allocation of limited health care resources.

We conducted a study to determine US national trends in use of ambulatory surgery for lateral epicondylitis. We focused on age, sex, surgical setting, anesthetic type, and payment method.

Methods

As the National Survey of Ambulatory Surgery³² (NSAS) is an administrative dataset in which all data are deidentified and available for public use, this study was exempt from requiring institutional review board approval.

NSAS data were used to analyze trends in treatment of lateral epicondylitis between 1994 and 2006. NSAS was undertaken by the National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention (CDC) to obtain information about the use of ambulatory surgery in the United States. Since the early 1980s, ambulatory surgery has increased in the United States because of advances in medical technology and cost-containment initiatives.³³ The number of procedures being performed in ambulatory surgery centers increased from 31.5 million in 1996 to 53.3 million in 2006.³⁴ Funded by the CDC, NSAS is a national study that involves both hospital-based and freestanding ambulatory surgery centers and provides the most recent and comprehensive overview of ambulatory surgery in the United States.³⁵ Because of budgetary limitations, 2006 was the last year in which data for NSAS were collected. Data for NSAS come from Medicare-participating, noninstitutional hospitals (excluding military hospitals, federal facilities, and Veteran Affairs hospitals) in all 50 states and the District of Columbia with a minimum of 6 beds staffed for patient use. NSAS used only short-stay hospitals (hospitals with an average length of stay for all patients of less than 30 days) or hospitals that had a specialty of general (medical or surgical) or children’s general. NSAS was conducted in 1994, 1996, and 2006 with medical information recorded on patient abstracts coded by contract staff. NSAS selected a sample of ambulatory surgery visits using a systematic random sampling procedure, and selection of visits within each facility was done separately for each location where ambulatory surgery was performed. In 1994, 751 facilities were sampled, and 88% of hospitals responded. In 1996, 750 facilities were sampled, and 91% of hospitals responded. In 2006, 696 facilities were sampled, and 75% responded. The surveys used International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes³⁶ to classify medical diagnoses and procedures. To produce an unbiased national estimate, NCHS used multistage estimate procedures, including inflation by reciprocals of the probabilities of sample selection, population-weighting ratio adjustments, and adjustment for no response.³⁷

Demographic and medical information was obtained for people with an ICD-9-CM diagnosis code of lateral epicondylitis (726.32), using previously described techniques.³⁸ Data were then recorded for age, sex, facility type, insurance type, anesthesia type, diagnoses, and procedures.

Descriptive statistics consisted of means and standard deviations for continuous variables and frequency and percentages for discrete variables. Because NSAS data were collected on the basis of a probabilistic sample scheme, they were analyzed using a sampling weighting method. Sampling weights (inverse of selection probability) provided by the CDC were used to account for unequal sampling probabilities and to produce estimates for all visits in the United States. A Taylor linearization model provided by the CDC estimates was used to calculate standard error and confidence intervals (CIs) of the data. Standard error is a measure of sampling variability that occurs by chance because only a sample rather than the entire universe is surveyed. To define population parameters, NCHS chose 95% CIs along with a point estimate. Direct statistical comparison between years cannot be performed because of sampling differences in the database compared between years. The CIs, however, can suggest statistical differences if the data are nonoverlapping. US census data were used to obtain national population estimates for each year of the study (1994, 1996, 2006).³⁹ Rates were presented as number of procedures per 100,000 standard population. For age, a direct adjustment procedure was used, and the US population in 2000 was selected as the standard population. Applying sex-specific rates to the standard population and dividing by the total in the standard population, we calculated sex-adjusted rates for each year. All data were analyzed using SPSS Version 20 software.

Results

A total of 30,311 ambulatory surgical procedures (95% CI, 27,292-33,330) or 10.44 per 100,000 capita were recorded by NSAS for the treatment of lateral epicondylitis in 2006 (Table 1). This represents a large increase in the total number of ambulatory procedures, from 21,852 in 1994 (95% CI, 19,981-23,722; 7.29/100,000) and 20,372 in 1996 (95% CI, 18,660-22,083; 6.73/100,000).

Between 1994 and 2006, the sex-adjusted rate of ambulatory surgery for lateral epicondylitis increased by 85% among females (7.74/100,000 to 14.31/100,000), whereas the rate decreased by 31% among males (8.07/100,000 to 5.59/100,000) (Table 1). The age-adjusted rate of ambulatory surgery for lateral epicondylitis increased among all age groups except the 30–39 years group (Table 2). The largest increase in age-adjusted rates was found for patients older than 50 years (275%) between 1994 and 2006.

During the study period, use of regional anesthesia nearly doubled, from 17% to 30%, whereas use of general anesthesia decreased, from 69% to 57% (Table 3). At all time points, the most common procedure performed for lateral epicondylitis in ambulatory surgery centers was division/release of the joint capsule of the elbow (Table 4). Private insurance remained the most common source of payment for all study years, ranging from 52% to 60% (Table 5). The Figure shows that, between 1994 and 2006, the proportion of surgeries performed in a freestanding ambulatory center increased.

Discussion

In this descriptive epidemiologic study, we used NSAS data to investigate trends in ambulatory surgery for lateral epicondylitis between 1994 and 2006.³² Our results showed that total number of procedures and the population-adjusted rate of procedures for lateral epicondylitis increased during the study period. The largest increase in age-adjusted rates of surgery for lateral epicondylitis was found among patients older than 50 years, whereas the highest age-adjusted rate of ambulatory surgery for lateral epicondylitis was found among patients between ages 40 and 49 years. These findings are similar to those of previous studies, which have shown that most patients with lateral epicondylitis present in the fourth and fifth decades of life.²² Prior reports have suggested that the incidence of lateral epicondylitis in men and women is equal.²² The present study found a change in sex-adjusted rates of ambulatory surgery for lateral epicondylitis between 1994 and 2006. Specifically, in 1994, surgery rates for men and women were similar (8.07/100,000 and 7.74/100,000), but in 2006 the sex-adjusted rate of surgery for lateral epicondylitis was almost 3 times higher for women than for men (14.31/100,000 vs 5.59/100,000).

We also found that the population-adjusted rate of lateral epicondylectomy increased drastically, from 0.4 per 100,000 in 1994 to 3.53 per 100,000 in 2006. Lateral epicondylectomy involves excision of the tip of the lateral epicondyle (typically, 0.5 cm) to produce a cancellous bone surface to which the edges of the débrided extensor tendon can be approximated without tension.²³ It is possible that the increased rate of lateral epicondylectomy reflects evidence-based practice changes during the study period,²⁷ though denervation was found more favorable than epicondylectomy in a recent study by Berry and colleagues.⁴⁰ Future studies should investigate whether rates of epicondylectomy have changed since 2006. In addition, the present study showed a correlation between the introduction of arthroscopic techniques for the treatment of lateral epicondylitis and the period when much research was being conducted on the topic.^24,25,28 As arthroscopic techniques improve, their rates are likely to continue to increase.

Our results also showed an increase in procedures performed in freestanding facilities. The rise in ambulatory surgical volume, speculated to result from more procedures being performed in freestanding facilities,³⁴ has been reported with knee and shoulder arthroscopy.⁴¹ In addition, though general anesthesia remained the most used technique, our results showed a shift toward peripheral nerve blocks. The increase in regional anesthesia, which has also been noted in joint arthroscopy, is thought to stem from the advent of nerve-localizing technology, such as nerve stimulation and ultrasound guidance.⁴¹ Peripheral nerve blocks are favorable on both economic and quality measures, are associated with fewer opioid-related side effects, and overall provide better analgesia in comparison with opioids, highlighting their importance in the ambulatory setting.⁴²

Although large, national databases are well suited to epidemiologic research,⁴³ our study had limitations. As with all databases, NSAS is subject to data entry errors and coding errors.^44,45 However, the database administrators corrected for this by using a multistage estimate procedure with weighting adjustments for no response and population-weighting ratio adjustments.³⁵ Another limitation of this study is its lack of clinical detail, as procedure codes are general and do not allow differentiation between specific patients. Because of the retrospective nature of the analysis and the heterogeneity of the data, assessment of specific surgeries for lateral epicondylitis was limited. Although a strength of using NSAS to perform epidemiologic analyses is its large sample size, this also sacrifices specificity in terms of clinical insight. The results of this study may influence investigations to distinguish differences between procedures used in the treatment of lateral epicondylitis. Furthermore, the results of this study are limited to ambulatory surgery practice patterns in the United States between 1996 and 2006. Last, our ability to perform economic analyses was limited, as data on total hospital cost were not recorded by the surveys.

Conclusion

The increase in ambulatory surgery for lateral epicondylitis, demonstrated in this study, emphasizes the importance of national funding for surveys such as NSAS beyond 2006, as utilization trends may have considerable effects on health care policies that influence the quality of patient care.

First described by Runge¹ in 1873 and later termed lawn-tennis arm by Major² in 1883, lateral epicondylitis is a common cause of elbow pain, affecting 1% to 3% of the general population each year.^3,4 Given that prevalence estimates are up to 15% among workers in repetitive hand task industries,^5-7 symptoms of lateral epicondylitis are thought to be related to recurring wrist extension and alternating forearm pronation and supination.⁸ Between 80% and 90% of patients with lateral epicondylitis experience symptomatic improvement with conservative therapy,^9-11 including rest and use of nonsteroidal anti-inflammatory medications,¹² physical therapy,^13,14 corticosteroid injections,^10,15,16 orthoses,^17,18 and shock wave therapy.¹⁹ However, between 4% and 11% of patients with newly diagnosed lateral epicondylitis do not respond to prolonged (6- to 12-month) conservative treatment and then require operative intervention,^11,20,21 with some referral practices reporting rates as high as 25%.²²

Traditionally, operative management of lateral epicondylitis involved open débridement of the extensor carpi radialis brevis (ECRB).^11,20 More recently, the spectrum of operations for lateral epicondylitis has expanded to include procedures that repair the extensor origin after débridement of the torn tendon and angiofibroblastic dysplasia; procedures that use fasciotomy or direct release of the extensor origin from the epicondyle to relieve tension on the common extensor; procedures directed at the radial or posterior interosseous nerve; and procedures that use arthroscopic techniques to divide the orbicular ligament, reshape the radial head, or release the extensor origin.²³ There has been debate about the value of repairing the ECRB, lengthening the ECRB, simultaneously decompressing the radial nerve or resecting epicondylar bone, and performing the procedures percutaneously, endoscopically, or arthroscopically.^24-28 Despite multiple studies of the outcomes of these procedures,^11,29-31 little is known regarding US national trends for operative treatment of lateral epicondylitis. Understanding national practice patterns and disease burden is essential to allocation of limited health care resources.

We conducted a study to determine US national trends in use of ambulatory surgery for lateral epicondylitis. We focused on age, sex, surgical setting, anesthetic type, and payment method.

Methods

As the National Survey of Ambulatory Surgery³² (NSAS) is an administrative dataset in which all data are deidentified and available for public use, this study was exempt from requiring institutional review board approval.

NSAS data were used to analyze trends in treatment of lateral epicondylitis between 1994 and 2006. NSAS was undertaken by the National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention (CDC) to obtain information about the use of ambulatory surgery in the United States. Since the early 1980s, ambulatory surgery has increased in the United States because of advances in medical technology and cost-containment initiatives.³³ The number of procedures being performed in ambulatory surgery centers increased from 31.5 million in 1996 to 53.3 million in 2006.³⁴ Funded by the CDC, NSAS is a national study that involves both hospital-based and freestanding ambulatory surgery centers and provides the most recent and comprehensive overview of ambulatory surgery in the United States.³⁵ Because of budgetary limitations, 2006 was the last year in which data for NSAS were collected. Data for NSAS come from Medicare-participating, noninstitutional hospitals (excluding military hospitals, federal facilities, and Veteran Affairs hospitals) in all 50 states and the District of Columbia with a minimum of 6 beds staffed for patient use. NSAS used only short-stay hospitals (hospitals with an average length of stay for all patients of less than 30 days) or hospitals that had a specialty of general (medical or surgical) or children’s general. NSAS was conducted in 1994, 1996, and 2006 with medical information recorded on patient abstracts coded by contract staff. NSAS selected a sample of ambulatory surgery visits using a systematic random sampling procedure, and selection of visits within each facility was done separately for each location where ambulatory surgery was performed. In 1994, 751 facilities were sampled, and 88% of hospitals responded. In 1996, 750 facilities were sampled, and 91% of hospitals responded. In 2006, 696 facilities were sampled, and 75% responded. The surveys used International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes³⁶ to classify medical diagnoses and procedures. To produce an unbiased national estimate, NCHS used multistage estimate procedures, including inflation by reciprocals of the probabilities of sample selection, population-weighting ratio adjustments, and adjustment for no response.³⁷

Demographic and medical information was obtained for people with an ICD-9-CM diagnosis code of lateral epicondylitis (726.32), using previously described techniques.³⁸ Data were then recorded for age, sex, facility type, insurance type, anesthesia type, diagnoses, and procedures.

Descriptive statistics consisted of means and standard deviations for continuous variables and frequency and percentages for discrete variables. Because NSAS data were collected on the basis of a probabilistic sample scheme, they were analyzed using a sampling weighting method. Sampling weights (inverse of selection probability) provided by the CDC were used to account for unequal sampling probabilities and to produce estimates for all visits in the United States. A Taylor linearization model provided by the CDC estimates was used to calculate standard error and confidence intervals (CIs) of the data. Standard error is a measure of sampling variability that occurs by chance because only a sample rather than the entire universe is surveyed. To define population parameters, NCHS chose 95% CIs along with a point estimate. Direct statistical comparison between years cannot be performed because of sampling differences in the database compared between years. The CIs, however, can suggest statistical differences if the data are nonoverlapping. US census data were used to obtain national population estimates for each year of the study (1994, 1996, 2006).³⁹ Rates were presented as number of procedures per 100,000 standard population. For age, a direct adjustment procedure was used, and the US population in 2000 was selected as the standard population. Applying sex-specific rates to the standard population and dividing by the total in the standard population, we calculated sex-adjusted rates for each year. All data were analyzed using SPSS Version 20 software.

Results

A total of 30,311 ambulatory surgical procedures (95% CI, 27,292-33,330) or 10.44 per 100,000 capita were recorded by NSAS for the treatment of lateral epicondylitis in 2006 (Table 1). This represents a large increase in the total number of ambulatory procedures, from 21,852 in 1994 (95% CI, 19,981-23,722; 7.29/100,000) and 20,372 in 1996 (95% CI, 18,660-22,083; 6.73/100,000).

Between 1994 and 2006, the sex-adjusted rate of ambulatory surgery for lateral epicondylitis increased by 85% among females (7.74/100,000 to 14.31/100,000), whereas the rate decreased by 31% among males (8.07/100,000 to 5.59/100,000) (Table 1). The age-adjusted rate of ambulatory surgery for lateral epicondylitis increased among all age groups except the 30–39 years group (Table 2). The largest increase in age-adjusted rates was found for patients older than 50 years (275%) between 1994 and 2006.

During the study period, use of regional anesthesia nearly doubled, from 17% to 30%, whereas use of general anesthesia decreased, from 69% to 57% (Table 3). At all time points, the most common procedure performed for lateral epicondylitis in ambulatory surgery centers was division/release of the joint capsule of the elbow (Table 4). Private insurance remained the most common source of payment for all study years, ranging from 52% to 60% (Table 5). The Figure shows that, between 1994 and 2006, the proportion of surgeries performed in a freestanding ambulatory center increased.

Discussion

In this descriptive epidemiologic study, we used NSAS data to investigate trends in ambulatory surgery for lateral epicondylitis between 1994 and 2006.³² Our results showed that total number of procedures and the population-adjusted rate of procedures for lateral epicondylitis increased during the study period. The largest increase in age-adjusted rates of surgery for lateral epicondylitis was found among patients older than 50 years, whereas the highest age-adjusted rate of ambulatory surgery for lateral epicondylitis was found among patients between ages 40 and 49 years. These findings are similar to those of previous studies, which have shown that most patients with lateral epicondylitis present in the fourth and fifth decades of life.²² Prior reports have suggested that the incidence of lateral epicondylitis in men and women is equal.²² The present study found a change in sex-adjusted rates of ambulatory surgery for lateral epicondylitis between 1994 and 2006. Specifically, in 1994, surgery rates for men and women were similar (8.07/100,000 and 7.74/100,000), but in 2006 the sex-adjusted rate of surgery for lateral epicondylitis was almost 3 times higher for women than for men (14.31/100,000 vs 5.59/100,000).

We also found that the population-adjusted rate of lateral epicondylectomy increased drastically, from 0.4 per 100,000 in 1994 to 3.53 per 100,000 in 2006. Lateral epicondylectomy involves excision of the tip of the lateral epicondyle (typically, 0.5 cm) to produce a cancellous bone surface to which the edges of the débrided extensor tendon can be approximated without tension.²³ It is possible that the increased rate of lateral epicondylectomy reflects evidence-based practice changes during the study period,²⁷ though denervation was found more favorable than epicondylectomy in a recent study by Berry and colleagues.⁴⁰ Future studies should investigate whether rates of epicondylectomy have changed since 2006. In addition, the present study showed a correlation between the introduction of arthroscopic techniques for the treatment of lateral epicondylitis and the period when much research was being conducted on the topic.^24,25,28 As arthroscopic techniques improve, their rates are likely to continue to increase.

Our results also showed an increase in procedures performed in freestanding facilities. The rise in ambulatory surgical volume, speculated to result from more procedures being performed in freestanding facilities,³⁴ has been reported with knee and shoulder arthroscopy.⁴¹ In addition, though general anesthesia remained the most used technique, our results showed a shift toward peripheral nerve blocks. The increase in regional anesthesia, which has also been noted in joint arthroscopy, is thought to stem from the advent of nerve-localizing technology, such as nerve stimulation and ultrasound guidance.⁴¹ Peripheral nerve blocks are favorable on both economic and quality measures, are associated with fewer opioid-related side effects, and overall provide better analgesia in comparison with opioids, highlighting their importance in the ambulatory setting.⁴²

Although large, national databases are well suited to epidemiologic research,⁴³ our study had limitations. As with all databases, NSAS is subject to data entry errors and coding errors.^44,45 However, the database administrators corrected for this by using a multistage estimate procedure with weighting adjustments for no response and population-weighting ratio adjustments.³⁵ Another limitation of this study is its lack of clinical detail, as procedure codes are general and do not allow differentiation between specific patients. Because of the retrospective nature of the analysis and the heterogeneity of the data, assessment of specific surgeries for lateral epicondylitis was limited. Although a strength of using NSAS to perform epidemiologic analyses is its large sample size, this also sacrifices specificity in terms of clinical insight. The results of this study may influence investigations to distinguish differences between procedures used in the treatment of lateral epicondylitis. Furthermore, the results of this study are limited to ambulatory surgery practice patterns in the United States between 1996 and 2006. Last, our ability to perform economic analyses was limited, as data on total hospital cost were not recorded by the surveys.

Conclusion

The increase in ambulatory surgery for lateral epicondylitis, demonstrated in this study, emphasizes the importance of national funding for surveys such as NSAS beyond 2006, as utilization trends may have considerable effects on health care policies that influence the quality of patient care.