All current health care initiatives, whether overseen by providers, insurers, Pharma, or other industries, are focused on patient engagement. This overused but important term implies the active participation of patients in their own care. It implies that patients have the best means and educational resources available to them. Traditionally, patient education is achieve via face-to-face discussions with the physician or nurse or via third-party, preprinted written materials. Even now, 70% of patients report getting their medical information from physicians or nurses, according to a survey by the Pew Internet Research Project.

That said, more and more patients are seeking health information online – 60% of U.S. adults reported doing so within the past year, the Pew survey found.

Patients and caregivers are now becoming mobile. Baby boomers are becoming “seniors” at the rate of 8,000 per day. Mobile health digital tools can take the form of apps, multimedia offerings of videos, printable patient instructions, disease state education, and follow-up appointment reminders. These can be done with proprietary third-party platforms, or SAAS (software as a service), or practice developed and available via a portal on a website. The reason for this lies in its relevancy and the critical need for education at that corner the patient and caregiver are turning. I will discuss five touch points that are important to the patient and optimal for delivering digital health tools.

• Office encounter for a new medical problem. When a patient is seen for a new clinical problem, there is a seemingly overwhelming amount of new information transmitted. This involves the definition and description of the diagnosis; the level of severity; implications for life expectancy, occupation, and lifestyle; and the impact on others. Often patients focus on the latter issues and not the medical aspects including treatment purpose, options, and impact. Much of what was discussed with them at the encounter is forgotten. After all, how much can patients learn in a 15-minute visit? The ability to furnish patients with a digital replay of their encounter, along with educational materials pertinent to a diagnosis or recommended testing/procedure, is appealing. A company with the technology to do that is Liberate Health. (Ed. note: This publication’s parent company has a relationship with Liberate Health. Dr. Scher leads Liberate’s Digital Clinician Advisory group.) Of course, not all patients learn the same way. Guidelines on how to choose the most effective patient education material have been updated by the National Institutes of Health.

• Seeing a new health care provider. Walking into a new physician’s office is always intimidating. The encounter includes exploring personalities while discussing the clinical aspects of the visit. Compatibility with regards to treatment philosophy should be of paramount concern to the patient. Discussion surrounding how the physician communicates with and supports the patient experience goes a long way in creating a good physician-patient relationship. The mention of digital tools to recommend (apps, links to reliable website) conveys empathy, which is critical to patient engagement.

• Recommendation for new therapy, test, or procedure. While a patient’s head is swimming thinking about what will be found and recommended after a test or procedure is discussed, specifics about the test itself can be lost. Support provided via easy-to-understand digital explanation and visuals, viewed at a patient’s convenience and shared with a caregiver, seem like a no-brainer.

• Hospital discharge. The hospital discharge process is a whirlwind of explanations, instructions, and hopefully, follow-up appointments. It is usually crammed into a few minutes. In one study, only 42% of patients being discharged were able to state their diagnosis or diagnoses and even fewer (37%) were able to identify the purpose of all the medications they were going home on (Mayo Clin. Proc. 2005;80:991-4). Another larger study describes the mismatch between thoroughness of written instructions and patient understanding (JAMA Intern. Med. 2013;173:1715-22). Again, digital instructions reviewed at a convenient time and place would facilitate understanding.

• Becoming a caregiver. No one teaches a family member how to become a caregiver. It’s even harder than becoming a parent which is often facilitated by observation while growing up. Caregiving is often thrust upon someone with an untimely diagnosis of a loved one. There is upheaval on emotional, physical, and logistical levels. Caregivers are critical in the adoption of mobile health technologies. They need to be included in the delivery of these tools for a couple of reasons: They will likely be more digital savvy than the elderly patient is, and they need to have accurate information to be a better caregiver. They are the “silent majority” of health care stakeholders and probably the most critical.

It is not difficult to see how digital technology tools can help the physician-patient relationship by making the patient a better partner in care. While adoption of these tools will not happen overnight, it will happen.

Dr. Scher is an electrophysiologist with the Heart Group of Lancaster (Pa.) General Health. He is also director of DLS Healthcare Consulting, Harrisburg, Pa., and clinical associate professor of medicine at the Pennsylvania State University, Hershey.

All current health care initiatives, whether overseen by providers, insurers, Pharma, or other industries, are focused on patient engagement. This overused but important term implies the active participation of patients in their own care. It implies that patients have the best means and educational resources available to them. Traditionally, patient education is achieve via face-to-face discussions with the physician or nurse or via third-party, preprinted written materials. Even now, 70% of patients report getting their medical information from physicians or nurses, according to a survey by the Pew Internet Research Project.

That said, more and more patients are seeking health information online – 60% of U.S. adults reported doing so within the past year, the Pew survey found.

Patients and caregivers are now becoming mobile. Baby boomers are becoming “seniors” at the rate of 8,000 per day. Mobile health digital tools can take the form of apps, multimedia offerings of videos, printable patient instructions, disease state education, and follow-up appointment reminders. These can be done with proprietary third-party platforms, or SAAS (software as a service), or practice developed and available via a portal on a website. The reason for this lies in its relevancy and the critical need for education at that corner the patient and caregiver are turning. I will discuss five touch points that are important to the patient and optimal for delivering digital health tools.

• Office encounter for a new medical problem. When a patient is seen for a new clinical problem, there is a seemingly overwhelming amount of new information transmitted. This involves the definition and description of the diagnosis; the level of severity; implications for life expectancy, occupation, and lifestyle; and the impact on others. Often patients focus on the latter issues and not the medical aspects including treatment purpose, options, and impact. Much of what was discussed with them at the encounter is forgotten. After all, how much can patients learn in a 15-minute visit? The ability to furnish patients with a digital replay of their encounter, along with educational materials pertinent to a diagnosis or recommended testing/procedure, is appealing. A company with the technology to do that is Liberate Health. (Ed. note: This publication’s parent company has a relationship with Liberate Health. Dr. Scher leads Liberate’s Digital Clinician Advisory group.) Of course, not all patients learn the same way. Guidelines on how to choose the most effective patient education material have been updated by the National Institutes of Health.

• Seeing a new health care provider. Walking into a new physician’s office is always intimidating. The encounter includes exploring personalities while discussing the clinical aspects of the visit. Compatibility with regards to treatment philosophy should be of paramount concern to the patient. Discussion surrounding how the physician communicates with and supports the patient experience goes a long way in creating a good physician-patient relationship. The mention of digital tools to recommend (apps, links to reliable website) conveys empathy, which is critical to patient engagement.

• Recommendation for new therapy, test, or procedure. While a patient’s head is swimming thinking about what will be found and recommended after a test or procedure is discussed, specifics about the test itself can be lost. Support provided via easy-to-understand digital explanation and visuals, viewed at a patient’s convenience and shared with a caregiver, seem like a no-brainer.

• Hospital discharge. The hospital discharge process is a whirlwind of explanations, instructions, and hopefully, follow-up appointments. It is usually crammed into a few minutes. In one study, only 42% of patients being discharged were able to state their diagnosis or diagnoses and even fewer (37%) were able to identify the purpose of all the medications they were going home on (Mayo Clin. Proc. 2005;80:991-4). Another larger study describes the mismatch between thoroughness of written instructions and patient understanding (JAMA Intern. Med. 2013;173:1715-22). Again, digital instructions reviewed at a convenient time and place would facilitate understanding.

• Becoming a caregiver. No one teaches a family member how to become a caregiver. It’s even harder than becoming a parent which is often facilitated by observation while growing up. Caregiving is often thrust upon someone with an untimely diagnosis of a loved one. There is upheaval on emotional, physical, and logistical levels. Caregivers are critical in the adoption of mobile health technologies. They need to be included in the delivery of these tools for a couple of reasons: They will likely be more digital savvy than the elderly patient is, and they need to have accurate information to be a better caregiver. They are the “silent majority” of health care stakeholders and probably the most critical.

It is not difficult to see how digital technology tools can help the physician-patient relationship by making the patient a better partner in care. While adoption of these tools will not happen overnight, it will happen.

Dr. Scher is an electrophysiologist with the Heart Group of Lancaster (Pa.) General Health. He is also director of DLS Healthcare Consulting, Harrisburg, Pa., and clinical associate professor of medicine at the Pennsylvania State University, Hershey.

All current health care initiatives, whether overseen by providers, insurers, Pharma, or other industries, are focused on patient engagement. This overused but important term implies the active participation of patients in their own care. It implies that patients have the best means and educational resources available to them. Traditionally, patient education is achieve via face-to-face discussions with the physician or nurse or via third-party, preprinted written materials. Even now, 70% of patients report getting their medical information from physicians or nurses, according to a survey by the Pew Internet Research Project.

That said, more and more patients are seeking health information online – 60% of U.S. adults reported doing so within the past year, the Pew survey found.

Patients and caregivers are now becoming mobile. Baby boomers are becoming “seniors” at the rate of 8,000 per day. Mobile health digital tools can take the form of apps, multimedia offerings of videos, printable patient instructions, disease state education, and follow-up appointment reminders. These can be done with proprietary third-party platforms, or SAAS (software as a service), or practice developed and available via a portal on a website. The reason for this lies in its relevancy and the critical need for education at that corner the patient and caregiver are turning. I will discuss five touch points that are important to the patient and optimal for delivering digital health tools.

• Office encounter for a new medical problem. When a patient is seen for a new clinical problem, there is a seemingly overwhelming amount of new information transmitted. This involves the definition and description of the diagnosis; the level of severity; implications for life expectancy, occupation, and lifestyle; and the impact on others. Often patients focus on the latter issues and not the medical aspects including treatment purpose, options, and impact. Much of what was discussed with them at the encounter is forgotten. After all, how much can patients learn in a 15-minute visit? The ability to furnish patients with a digital replay of their encounter, along with educational materials pertinent to a diagnosis or recommended testing/procedure, is appealing. A company with the technology to do that is Liberate Health. (Ed. note: This publication’s parent company has a relationship with Liberate Health. Dr. Scher leads Liberate’s Digital Clinician Advisory group.) Of course, not all patients learn the same way. Guidelines on how to choose the most effective patient education material have been updated by the National Institutes of Health.

• Seeing a new health care provider. Walking into a new physician’s office is always intimidating. The encounter includes exploring personalities while discussing the clinical aspects of the visit. Compatibility with regards to treatment philosophy should be of paramount concern to the patient. Discussion surrounding how the physician communicates with and supports the patient experience goes a long way in creating a good physician-patient relationship. The mention of digital tools to recommend (apps, links to reliable website) conveys empathy, which is critical to patient engagement.

• Recommendation for new therapy, test, or procedure. While a patient’s head is swimming thinking about what will be found and recommended after a test or procedure is discussed, specifics about the test itself can be lost. Support provided via easy-to-understand digital explanation and visuals, viewed at a patient’s convenience and shared with a caregiver, seem like a no-brainer.

• Hospital discharge. The hospital discharge process is a whirlwind of explanations, instructions, and hopefully, follow-up appointments. It is usually crammed into a few minutes. In one study, only 42% of patients being discharged were able to state their diagnosis or diagnoses and even fewer (37%) were able to identify the purpose of all the medications they were going home on (Mayo Clin. Proc. 2005;80:991-4). Another larger study describes the mismatch between thoroughness of written instructions and patient understanding (JAMA Intern. Med. 2013;173:1715-22). Again, digital instructions reviewed at a convenient time and place would facilitate understanding.

• Becoming a caregiver. No one teaches a family member how to become a caregiver. It’s even harder than becoming a parent which is often facilitated by observation while growing up. Caregiving is often thrust upon someone with an untimely diagnosis of a loved one. There is upheaval on emotional, physical, and logistical levels. Caregivers are critical in the adoption of mobile health technologies. They need to be included in the delivery of these tools for a couple of reasons: They will likely be more digital savvy than the elderly patient is, and they need to have accurate information to be a better caregiver. They are the “silent majority” of health care stakeholders and probably the most critical.

It is not difficult to see how digital technology tools can help the physician-patient relationship by making the patient a better partner in care. While adoption of these tools will not happen overnight, it will happen.

Dr. Scher is an electrophysiologist with the Heart Group of Lancaster (Pa.) General Health. He is also director of DLS Healthcare Consulting, Harrisburg, Pa., and clinical associate professor of medicine at the Pennsylvania State University, Hershey.

Cautery and radiofrequency ablation (RFA) devices are commonly used in shoulder arthroscopic surgery for hemostasis and ablation of soft tissue. Although these devices are easily used and applied, complications (eg, extensive release of deltoid muscle,¹ nerve damage,² tendon damage,³ cartilage damage from heat transfer⁴) can occur during arthroscopic surgery. Radiofrequency devices can elevate fluid temperatures to unsafe levels and directly or indirectly injure surrounding tissue.^5,6 Skin complications from using these devices include direct burns to the subcutaneous tissues from the joint to the skin surface⁷ and skin burns related to overheated arthroscopic fluid.⁸

In our English-language literature review, however, we found no report of a skin burn secondary to contact between a RFA device and a spinal needle used in identifying structures during an arthroscopic acromioplasty. We report such a case here. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 51-year-old woman injured her left, nondominant shoulder when a descending garage door hit her directly on the superior aspect of the shoulder. She had immediate onset of pain on the top and lateral side of the shoulder and was evaluated by a primary care physician. Radiographs and magnetic resonance imaging (MRI) were normal. The patient was referred to an orthopedic surgeon for further evaluation.

The orthopedic surgeon found her to be in good health, with no history of diabetes, vascular conditions, or skin disorders. The initial diagnosis after history taking and physical examination was impingement syndrome with subacromial bursitis. The surgeon recommended nonoperative treatment: ice, nonsteroidal anti-inflammatory drugs, and physical therapy. After 3 months, the patient’s examination was unchanged, and there was no improvement in pain. Cortisone injected into the subacromial space helped for a few weeks, but the pain returned. After 2 more cortisone injections over 9 months failed, repeat MRI showed no tears of the rotator cuff or any other salient abnormalities. The treatment options were discussed with the patient, and, because the physical examination findings were consistent with impingement syndrome and nonoperative measures had failed, she consented to arthroscopic evaluation of the shoulder and arthroscopic partial anterior-lateral acromioplasty.

The procedure was performed 8 months after initial injury. With the patient under general anesthesia and in a lateral decubitus position, her arm was placed in an arm holder. Before the partial acromioplasty, two 18-gauge spinal needles were inserted from the skin surface into the subacromial space to help localize the anterolateral acromion and the acromioclavicular joint. The procedure was performed with a pump using saline bags kept at room temperature. A bipolar radiofrequency device (Stryker Energy Radiofrequency Ablation System; Stryker, Mahwah, New Jersey) was used to débride the subacromial bursa and the periosteum of the undersurface of the acromion. While the bursa was being débrided, the radiofrequency device inadvertently touched the anterior lateral needle probe, and a small skin burn formed around the needle on the surface of the shoulder (Figure). The radiofrequency device did not directly contact the skin, and the deltoid fascia was intact. The spinal needle was removed, and the skin around the burn was excised; the muscle beneath the skin was intact and showed no signs of thermal damage. The skin was mobilized and closed with interrupted simple sutures using a 4-0 nylon suture. The procedure was then completed with no other complications.

After surgery, the patient recovered without complications, and the skin lesion healed with no signs of infection and no skin or muscle defects. Some stiffness was treated with medication and physical therapy. Nine months after surgery, the patient reported mild shoulder stiffness and remained dissatisfied with the appearance of the skin in the area of the burn.

Discussion

Our patient’s case is a reminder that contact between a radiofrequency device and metal needles can transfer heat to tissues and cause skin burns. When using a radiofrequency device around metal needles or cannulas, surgeons should be sure to avoid prolonged contact with the metal. Our patient’s case is the first reported case of a thermal skin injury occurring when a spinal needle was heated by an arthroscopic ablater.

Other authors have reported indirect thermal skin injuries caused by radiofrequency devices during arthroscopic surgery, but the causes were postulated to be direct contact between device and skin⁷ and overheating of the arthroscopy fluid.^5,6,8 Huang and colleagues⁸ reported that full-thickness skin burns occurred when normal saline used during routine knee arthroscopy overheated from use of a radiofrequency device. Burn lesions, noted on their patient’s leg within 1 day after surgery, required subsequent débridement, a muscle flap, and split-skin grafting. Skin burns caused by overheated fluid have occurred irrespective of type of fluid used (eg, 1.5% glycine or lactated Ringer solution).⁶ There was no evidence that our patient’s burn resulted from extravasated overheated fluid, as the lesion was localized to the area immediately around the needle and was not geographic, as was described by Huang and colleagues.⁸

Other possible causes of skin burns during arthroscopic surgery have been described, but none applies in our patient’s case. Segami and colleagues⁷ described a burn resulting from direct transfer of heat from the radiofrequency device to the skin because of their proximity. This mechanism was not the cause in our patient’s case; there was no evidence of a defect or burned deltoid muscle at time of surgery. Lau and Dao⁹ reported 2 small full-thickness skin burns caused by a fiberoptic-light cable tip placed on a patient’s leg; in addition, the hot (>170°C) cables caused the paper drapes to combust.⁹ Skin burns secondary to use of skin antiseptics have been reported,¹⁰ but such lesions typically are located beneath tourniquets or in areas of friction from surgical drapes. In some cases, lesions described as skin burns may actually have been pressure lesions secondary to moist skin and friction.¹¹

Whether type of radiofrequency device contributes to the occurrence of heat-related lesions during arthroscopic surgery is unknown. Some investigators have suggested there is more potential for harm with bipolar RFA devices than with monopolar devices.^12,13 Monopolar devices pass energy between a probe and a grounding plate, whereas bipolar devices pass energy through 2 points on the probe.¹⁴ Because the heat for the monopolar probe derives from the frictional resistance of tissues to each other rather than from the probe itself, the bipolar probe theoretically allows for better temperature control. In addition, bipolar probes require less current to achieve the same heating effect. However, recent studies have suggested that, compared with monopolar radiofrequency devices, bipolar radiofrequency devices are associated with larger increases in temperature at equal depths after an equal number of applications.^12,13

To our knowledge, no one has specifically investigated the type of bipolar device used in the present case. This case report, the first to describe a thermal skin injury caused by direct contact between a radiofrequency device and a metal needle inserted in the skin, is a reminder that contact between radiofrequency devices and spinal needles or other metal cannulas used in arthroscopic surgery should be avoided.

Cautery and radiofrequency ablation (RFA) devices are commonly used in shoulder arthroscopic surgery for hemostasis and ablation of soft tissue. Although these devices are easily used and applied, complications (eg, extensive release of deltoid muscle,¹ nerve damage,² tendon damage,³ cartilage damage from heat transfer⁴) can occur during arthroscopic surgery. Radiofrequency devices can elevate fluid temperatures to unsafe levels and directly or indirectly injure surrounding tissue.^5,6 Skin complications from using these devices include direct burns to the subcutaneous tissues from the joint to the skin surface⁷ and skin burns related to overheated arthroscopic fluid.⁸

In our English-language literature review, however, we found no report of a skin burn secondary to contact between a RFA device and a spinal needle used in identifying structures during an arthroscopic acromioplasty. We report such a case here. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 51-year-old woman injured her left, nondominant shoulder when a descending garage door hit her directly on the superior aspect of the shoulder. She had immediate onset of pain on the top and lateral side of the shoulder and was evaluated by a primary care physician. Radiographs and magnetic resonance imaging (MRI) were normal. The patient was referred to an orthopedic surgeon for further evaluation.

The orthopedic surgeon found her to be in good health, with no history of diabetes, vascular conditions, or skin disorders. The initial diagnosis after history taking and physical examination was impingement syndrome with subacromial bursitis. The surgeon recommended nonoperative treatment: ice, nonsteroidal anti-inflammatory drugs, and physical therapy. After 3 months, the patient’s examination was unchanged, and there was no improvement in pain. Cortisone injected into the subacromial space helped for a few weeks, but the pain returned. After 2 more cortisone injections over 9 months failed, repeat MRI showed no tears of the rotator cuff or any other salient abnormalities. The treatment options were discussed with the patient, and, because the physical examination findings were consistent with impingement syndrome and nonoperative measures had failed, she consented to arthroscopic evaluation of the shoulder and arthroscopic partial anterior-lateral acromioplasty.

The procedure was performed 8 months after initial injury. With the patient under general anesthesia and in a lateral decubitus position, her arm was placed in an arm holder. Before the partial acromioplasty, two 18-gauge spinal needles were inserted from the skin surface into the subacromial space to help localize the anterolateral acromion and the acromioclavicular joint. The procedure was performed with a pump using saline bags kept at room temperature. A bipolar radiofrequency device (Stryker Energy Radiofrequency Ablation System; Stryker, Mahwah, New Jersey) was used to débride the subacromial bursa and the periosteum of the undersurface of the acromion. While the bursa was being débrided, the radiofrequency device inadvertently touched the anterior lateral needle probe, and a small skin burn formed around the needle on the surface of the shoulder (Figure). The radiofrequency device did not directly contact the skin, and the deltoid fascia was intact. The spinal needle was removed, and the skin around the burn was excised; the muscle beneath the skin was intact and showed no signs of thermal damage. The skin was mobilized and closed with interrupted simple sutures using a 4-0 nylon suture. The procedure was then completed with no other complications.

After surgery, the patient recovered without complications, and the skin lesion healed with no signs of infection and no skin or muscle defects. Some stiffness was treated with medication and physical therapy. Nine months after surgery, the patient reported mild shoulder stiffness and remained dissatisfied with the appearance of the skin in the area of the burn.

Discussion

Our patient’s case is a reminder that contact between a radiofrequency device and metal needles can transfer heat to tissues and cause skin burns. When using a radiofrequency device around metal needles or cannulas, surgeons should be sure to avoid prolonged contact with the metal. Our patient’s case is the first reported case of a thermal skin injury occurring when a spinal needle was heated by an arthroscopic ablater.

Other authors have reported indirect thermal skin injuries caused by radiofrequency devices during arthroscopic surgery, but the causes were postulated to be direct contact between device and skin⁷ and overheating of the arthroscopy fluid.^5,6,8 Huang and colleagues⁸ reported that full-thickness skin burns occurred when normal saline used during routine knee arthroscopy overheated from use of a radiofrequency device. Burn lesions, noted on their patient’s leg within 1 day after surgery, required subsequent débridement, a muscle flap, and split-skin grafting. Skin burns caused by overheated fluid have occurred irrespective of type of fluid used (eg, 1.5% glycine or lactated Ringer solution).⁶ There was no evidence that our patient’s burn resulted from extravasated overheated fluid, as the lesion was localized to the area immediately around the needle and was not geographic, as was described by Huang and colleagues.⁸

Other possible causes of skin burns during arthroscopic surgery have been described, but none applies in our patient’s case. Segami and colleagues⁷ described a burn resulting from direct transfer of heat from the radiofrequency device to the skin because of their proximity. This mechanism was not the cause in our patient’s case; there was no evidence of a defect or burned deltoid muscle at time of surgery. Lau and Dao⁹ reported 2 small full-thickness skin burns caused by a fiberoptic-light cable tip placed on a patient’s leg; in addition, the hot (>170°C) cables caused the paper drapes to combust.⁹ Skin burns secondary to use of skin antiseptics have been reported,¹⁰ but such lesions typically are located beneath tourniquets or in areas of friction from surgical drapes. In some cases, lesions described as skin burns may actually have been pressure lesions secondary to moist skin and friction.¹¹

Whether type of radiofrequency device contributes to the occurrence of heat-related lesions during arthroscopic surgery is unknown. Some investigators have suggested there is more potential for harm with bipolar RFA devices than with monopolar devices.^12,13 Monopolar devices pass energy between a probe and a grounding plate, whereas bipolar devices pass energy through 2 points on the probe.¹⁴ Because the heat for the monopolar probe derives from the frictional resistance of tissues to each other rather than from the probe itself, the bipolar probe theoretically allows for better temperature control. In addition, bipolar probes require less current to achieve the same heating effect. However, recent studies have suggested that, compared with monopolar radiofrequency devices, bipolar radiofrequency devices are associated with larger increases in temperature at equal depths after an equal number of applications.^12,13

To our knowledge, no one has specifically investigated the type of bipolar device used in the present case. This case report, the first to describe a thermal skin injury caused by direct contact between a radiofrequency device and a metal needle inserted in the skin, is a reminder that contact between radiofrequency devices and spinal needles or other metal cannulas used in arthroscopic surgery should be avoided.

Cautery and radiofrequency ablation (RFA) devices are commonly used in shoulder arthroscopic surgery for hemostasis and ablation of soft tissue. Although these devices are easily used and applied, complications (eg, extensive release of deltoid muscle,¹ nerve damage,² tendon damage,³ cartilage damage from heat transfer⁴) can occur during arthroscopic surgery. Radiofrequency devices can elevate fluid temperatures to unsafe levels and directly or indirectly injure surrounding tissue.^5,6 Skin complications from using these devices include direct burns to the subcutaneous tissues from the joint to the skin surface⁷ and skin burns related to overheated arthroscopic fluid.⁸

In our English-language literature review, however, we found no report of a skin burn secondary to contact between a RFA device and a spinal needle used in identifying structures during an arthroscopic acromioplasty. We report such a case here. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 51-year-old woman injured her left, nondominant shoulder when a descending garage door hit her directly on the superior aspect of the shoulder. She had immediate onset of pain on the top and lateral side of the shoulder and was evaluated by a primary care physician. Radiographs and magnetic resonance imaging (MRI) were normal. The patient was referred to an orthopedic surgeon for further evaluation.

The orthopedic surgeon found her to be in good health, with no history of diabetes, vascular conditions, or skin disorders. The initial diagnosis after history taking and physical examination was impingement syndrome with subacromial bursitis. The surgeon recommended nonoperative treatment: ice, nonsteroidal anti-inflammatory drugs, and physical therapy. After 3 months, the patient’s examination was unchanged, and there was no improvement in pain. Cortisone injected into the subacromial space helped for a few weeks, but the pain returned. After 2 more cortisone injections over 9 months failed, repeat MRI showed no tears of the rotator cuff or any other salient abnormalities. The treatment options were discussed with the patient, and, because the physical examination findings were consistent with impingement syndrome and nonoperative measures had failed, she consented to arthroscopic evaluation of the shoulder and arthroscopic partial anterior-lateral acromioplasty.

The procedure was performed 8 months after initial injury. With the patient under general anesthesia and in a lateral decubitus position, her arm was placed in an arm holder. Before the partial acromioplasty, two 18-gauge spinal needles were inserted from the skin surface into the subacromial space to help localize the anterolateral acromion and the acromioclavicular joint. The procedure was performed with a pump using saline bags kept at room temperature. A bipolar radiofrequency device (Stryker Energy Radiofrequency Ablation System; Stryker, Mahwah, New Jersey) was used to débride the subacromial bursa and the periosteum of the undersurface of the acromion. While the bursa was being débrided, the radiofrequency device inadvertently touched the anterior lateral needle probe, and a small skin burn formed around the needle on the surface of the shoulder (Figure). The radiofrequency device did not directly contact the skin, and the deltoid fascia was intact. The spinal needle was removed, and the skin around the burn was excised; the muscle beneath the skin was intact and showed no signs of thermal damage. The skin was mobilized and closed with interrupted simple sutures using a 4-0 nylon suture. The procedure was then completed with no other complications.

After surgery, the patient recovered without complications, and the skin lesion healed with no signs of infection and no skin or muscle defects. Some stiffness was treated with medication and physical therapy. Nine months after surgery, the patient reported mild shoulder stiffness and remained dissatisfied with the appearance of the skin in the area of the burn.

Discussion

Our patient’s case is a reminder that contact between a radiofrequency device and metal needles can transfer heat to tissues and cause skin burns. When using a radiofrequency device around metal needles or cannulas, surgeons should be sure to avoid prolonged contact with the metal. Our patient’s case is the first reported case of a thermal skin injury occurring when a spinal needle was heated by an arthroscopic ablater.

Other authors have reported indirect thermal skin injuries caused by radiofrequency devices during arthroscopic surgery, but the causes were postulated to be direct contact between device and skin⁷ and overheating of the arthroscopy fluid.^5,6,8 Huang and colleagues⁸ reported that full-thickness skin burns occurred when normal saline used during routine knee arthroscopy overheated from use of a radiofrequency device. Burn lesions, noted on their patient’s leg within 1 day after surgery, required subsequent débridement, a muscle flap, and split-skin grafting. Skin burns caused by overheated fluid have occurred irrespective of type of fluid used (eg, 1.5% glycine or lactated Ringer solution).⁶ There was no evidence that our patient’s burn resulted from extravasated overheated fluid, as the lesion was localized to the area immediately around the needle and was not geographic, as was described by Huang and colleagues.⁸

Other possible causes of skin burns during arthroscopic surgery have been described, but none applies in our patient’s case. Segami and colleagues⁷ described a burn resulting from direct transfer of heat from the radiofrequency device to the skin because of their proximity. This mechanism was not the cause in our patient’s case; there was no evidence of a defect or burned deltoid muscle at time of surgery. Lau and Dao⁹ reported 2 small full-thickness skin burns caused by a fiberoptic-light cable tip placed on a patient’s leg; in addition, the hot (>170°C) cables caused the paper drapes to combust.⁹ Skin burns secondary to use of skin antiseptics have been reported,¹⁰ but such lesions typically are located beneath tourniquets or in areas of friction from surgical drapes. In some cases, lesions described as skin burns may actually have been pressure lesions secondary to moist skin and friction.¹¹

Whether type of radiofrequency device contributes to the occurrence of heat-related lesions during arthroscopic surgery is unknown. Some investigators have suggested there is more potential for harm with bipolar RFA devices than with monopolar devices.^12,13 Monopolar devices pass energy between a probe and a grounding plate, whereas bipolar devices pass energy through 2 points on the probe.¹⁴ Because the heat for the monopolar probe derives from the frictional resistance of tissues to each other rather than from the probe itself, the bipolar probe theoretically allows for better temperature control. In addition, bipolar probes require less current to achieve the same heating effect. However, recent studies have suggested that, compared with monopolar radiofrequency devices, bipolar radiofrequency devices are associated with larger increases in temperature at equal depths after an equal number of applications.^12,13

To our knowledge, no one has specifically investigated the type of bipolar device used in the present case. This case report, the first to describe a thermal skin injury caused by direct contact between a radiofrequency device and a metal needle inserted in the skin, is a reminder that contact between radiofrequency devices and spinal needles or other metal cannulas used in arthroscopic surgery should be avoided.

Deep infection in the presence of an implant after open reduction and internal fixation (ORIF) is usually treated with removal of the implant, serial débridement procedures, lavage, intravenously administered antibiotics, and, in some cases, placement of antibiotic-impregnated beads. If infection occurs during the early stages of bone healing, stabilization of the fractures might be compromised after removal of the implant. Although antibiotic-impregnated beads offer local delivery of antibiotics, they do not provide structural support of the fracture site. The beads often are difficult to remove after in-growth of granulation tissue. In areas of subcutaneous bone, an antibiotic bead pouch might be preferred to an open wound. Published research regarding the use of antibiotic-coated plates during the acute or chronic stages of infection is scarce. Plates offer the versatility of fracture stabilization, and the addition of antibiotic cement to the plates might aid in eradication of infection without necessitating a second surgery for removal. The patients provided written informed consent for print and electronic publication of these case reports.

Technique

After removal of implants, we perform débridement of the soft tissues with a hydroscalpel (Versajet; Smith & Nephew, London, United Kingdom), mechanical débridement of bone, and curettage with high speed burr. The wound is then irrigated with pulse pressure lavage and a minimum of 3 L sterile normal saline. The extremity is re-prepped and re-draped; the entire surgical team’s gowns and gloves are changed; and new instrumentation, including cautery and suction equipment, is used. The cement is prepared with tobramycin (3.6 g) and vancomycin (1 g) per 40-g bag of cement. The plate is placed in silicon tubing, and the antibiotic-prepared cement is injected into the tubing and molded until dry. Care is taken to mold the locations of the screw holes by making incisions in the tubing at the appropriate locations. Screws are placed through the screw holes to ensure locking capability, and Kirschner wires are placed through temporary fixation holes (Figure 1). Once dry, the screws and wires are removed from the plate, and the cement-coated plate is removed from the tubing. The antibiotic-coated plate is applied to the fracture or osteotomy site and is seated with screws as appropriate (Figure 2). The wound is closed primarily. Wound drains or vacuum-assisted closure devices are not routinely used unless there is high risk for hematoma formation. The authors prefer to have high local concentrations of antibiotic in the surrounding tissues and wound.

Clinical Series

Case 1

A 31-year-old man fell from a ladder and sustained a bimalleolar ankle fracture-dislocation that was treated with ORIF. Three weeks after initial injury, the patient presented with an infected lateral wound with purulent discharge. He was taken to the operating room for initial débridement, irrigation, and fracture stabilization with an antibiotic-coated plate and tension-band wiring of the medial malleoli. He was discharged from the hospital on day 4 after admission. Cultures of the wound grew beta-hemolytic strep group G and coagulase-negative staphylococci in broth that was sensitive to oxacillin, vancomycin, and gentamycin. The patient was treated with a 6-week regimen of Unasyn (Roerig, New York, New York), developed bony union, and has been free of clinical signs of infection for 2 years (Figures 3, 4).

Case 2

A 27-year-old male carpenter fell from a height of 12 feet and sustained a fracture of the distal radius that was treated with external fixation. The proximal pin site became clinically infected and subsequently developed osteomyelitis. The patient had a draining wound with a fracture for 2 months. He underwent débridement with partial resection of the radius and placement of an antibiotic cement–coated plate and calcium phosphate bone-void filler impregnated with antibiotics. Pathology specimens were positive for osteomyelitis, and bone cultures showed methicillin-sensitive Staphylococcus aureus (MSSA). He received intravenously administered antibiotic therapy for 6 weeks after surgery. The patient has remained free of clinical signs of infection for more than 1 year and has achieved bony union (Figures 5A, 5B).

Case 3

A 44-year-old woman with insulin-dependent diabetes mellitus and venous stasis sustained a trimalleolar ankle fracture after a low-energy fall that was initially treated with ORIF. She underwent revision ORIF to treat a malunion 3 months after initial treatment. At 8 months, the patient developed a draining sinus communicating with the plate. Computed tomography revealed nonunion and indicated infection. The patient underwent resection of the osteomyelitis and repair of the fibular nonunion with an antibiotic-coated plate. Tissue cultures were positive for coagulase-negative staphylococcus, and pathology specimens were positive for osteomyelitis. She received postoperative antibiotics intravenously and 6 weeks of antibiotic therapy after discharge from the hospital. The patient has remained free of clinical signs of infection for more than 1 year and has achieved bony union (Figures 6, 7).

Case 4

A 48-year-old man sustained an open olecranon fracture in another country. The fracture was initially treated with 1 dose of intravenously administered antibiotics and 5 days of orally administered antibiotics. The patient returned to the United States and was treated with intravenously administered antibiotics for cellulitis of the elbow for 11 days before referral to our institution, where he underwent ORIF with placement of an antibiotic-coated plate and tension-band wiring. Soft-tissue and bone cultures had no growth. He received intravenously administered antibiotics for 6 weeks. At 5 months postoperatively, the plate was removed because of pain. The patient has remained free of clinical signs of infection for more than 1 year and has achieved bony union (Figures 8A-8C).

Discussion

Acute infections of fractures have recently been treated with success by Berkes and colleagues,¹ who reported a 71% union rate achieved with operative débridement, antibiotic suppression, and retention of fixation until fracture union occurs. The study by Berkes and colleagues¹ had a small patient population, and larger cohorts are needed to show more reliable results; however, this treatment maintains structural support for the fracture during healing but requires multiple trips to the operating room for débridements as well as the use of systemic intravenous antibiotic therapy.

A technique that was developed by the primary author (Janet D. Conway, MD) and has not been described in the literature allows for use of antibiotic cement–coated plates to treat early postoperative infections and osteomyelitic nonunions. This approach permits fracture stabilization and local delivery of high concentrations of broad-spectrum antibiotics and can reduce the number of débridement procedures required in the operating room. We present a technique that includes the use of antibiotic cement–coated plates to treat early postoperative infections associated with fractures and nonunions in order to provide eradication of infection and bony stabilization.

Our approach parallels the current theory that treating infection at a site of union is preferable to treating infection at a site of nonunion.¹ Fixation devices should remain in place until osseous union is achieved. With the addition of antibiotics to the plate, removal might not be necessary unless a device is loose, nonfunctional, or, ultimately, causing pain. Other options, such as external fixation, can be burdensome to patients and can be associated with other risks. One of our 4 patients required fixation removal because of pain at the elbow; however, even noncoated olecranon plates typically are removed because of pain after fracture healing. Antibiotic cement adds bulk to the construct and can become very prominent in areas of little soft-tissue coverage (Figure 9).

Studies, assessing variables that correlate with higher likelihood of failure for primary repairs, have shown that open fracture, use of an intramedullary nail, and smoking are the highest risk factors for infected nonunion.¹⁻⁴ Among our 4 patients, 3 were smokers and 1 originally had an open fracture. Smokers have been found to have a 37% higher nonunion rate and are 2 times more likely to develop wound infection and osteomyelitis.^1,5 More than 60% of the time, infections are caused by S aureus or coagulase-negative staphylococci.^1,5,6 In our study population, 3 of the 4 patients had coagulase-negative staphylococci grow in the cultures. Implants infected with S aureus or Candida require surgical removal. Those with less virulent coagulase-negative staphylococci might not necessitate removal; however, our population had had antibiotic therapy and continued draining sinus.⁵ Rightmire and colleagues⁷ reported that those who develop infection earlier than 16 weeks postoperatively have a 68% success rate and that smoking is a major risk factor for infection. Development of Pseudomonas in the wound has been shown to have a positive correlation with amputation.^1,2 Infection with Pseudomonas, smoking, and involvement of the femur, tibia, ankle, or foot tended to result in failure.^1,2 Being clinically free of signs of infection after 3 months offers a 50% cure rate, with 78% at 6 months and 95% after 1 year.²

When determining an antibiotic to use with the polymethylmethacrylate (PMMA) cement, many factors must be considered, including spectrum, heat stability, and elution characteristics.⁸ A synergistic effect has been seen with combinations of antibiotics (eg, vancomycin and tobramycin used together). Vancomycin concentrations increased by 103% and tobramycin by 68% when used together compared with their elution rates when used alone, showing passive opportunism.⁹ This will, in essence, increase concentrations of antibiotics at the site locally, which will increase the bacteriocidal potential but also create a larger antimicrobial spectrum.⁹

The authors used Cobalt Bone Cement (Biomet Orthopedics, Inc, Warsaw, Indiana) which been shown to have higher elution properties than Simplex P Bone Cement (Stryker, Kalamazoo, Michigan).^3,10 The majority of elution occurs in the first 3 to 5 days but can continue for weeks after implantation. We place the cement on the plate allowing for its retention, hoping to eliminate a second surgery for removal.⁸ We recommend 3.6 g of tobramycin, and 1 g of vancomycin per 40-g bag of PMMA.³ This dose has been shown to be safe in respect to renal toxicity, plus the entire dose is not administered in a single setting because only a small portion of the cement is used when coating the plate. We close all wounds primarily, and do not regularly use drains or vacuum-assisted closures to help prevent a decrease in the local concentration of the antibiotics.¹¹

Broad-spectrum antibiotics are used to coat the plate in order to cover as many microbial organisms as possible without knowing the final offending organism. In our experience, this current technique provides antibiotic delivery with bony stability, therefore eliminating the need for multiple sequential surgical procedures. This difficult patient problem does not occur with enough frequency to warrant a large randomized clinical trial. However, this technique has been effective in these cases and may be useful to orthopedic surgeons in the future.

Conclusion

Based on our experience, early aggressive débridement, coupled with broad-spectrum antibiotic cement–coated plate insertion, provides fracture stability and helps eradicate the infection with 1 surgical procedure.

Deep infection in the presence of an implant after open reduction and internal fixation (ORIF) is usually treated with removal of the implant, serial débridement procedures, lavage, intravenously administered antibiotics, and, in some cases, placement of antibiotic-impregnated beads. If infection occurs during the early stages of bone healing, stabilization of the fractures might be compromised after removal of the implant. Although antibiotic-impregnated beads offer local delivery of antibiotics, they do not provide structural support of the fracture site. The beads often are difficult to remove after in-growth of granulation tissue. In areas of subcutaneous bone, an antibiotic bead pouch might be preferred to an open wound. Published research regarding the use of antibiotic-coated plates during the acute or chronic stages of infection is scarce. Plates offer the versatility of fracture stabilization, and the addition of antibiotic cement to the plates might aid in eradication of infection without necessitating a second surgery for removal. The patients provided written informed consent for print and electronic publication of these case reports.

Technique

After removal of implants, we perform débridement of the soft tissues with a hydroscalpel (Versajet; Smith & Nephew, London, United Kingdom), mechanical débridement of bone, and curettage with high speed burr. The wound is then irrigated with pulse pressure lavage and a minimum of 3 L sterile normal saline. The extremity is re-prepped and re-draped; the entire surgical team’s gowns and gloves are changed; and new instrumentation, including cautery and suction equipment, is used. The cement is prepared with tobramycin (3.6 g) and vancomycin (1 g) per 40-g bag of cement. The plate is placed in silicon tubing, and the antibiotic-prepared cement is injected into the tubing and molded until dry. Care is taken to mold the locations of the screw holes by making incisions in the tubing at the appropriate locations. Screws are placed through the screw holes to ensure locking capability, and Kirschner wires are placed through temporary fixation holes (Figure 1). Once dry, the screws and wires are removed from the plate, and the cement-coated plate is removed from the tubing. The antibiotic-coated plate is applied to the fracture or osteotomy site and is seated with screws as appropriate (Figure 2). The wound is closed primarily. Wound drains or vacuum-assisted closure devices are not routinely used unless there is high risk for hematoma formation. The authors prefer to have high local concentrations of antibiotic in the surrounding tissues and wound.

Clinical Series

Case 1

A 31-year-old man fell from a ladder and sustained a bimalleolar ankle fracture-dislocation that was treated with ORIF. Three weeks after initial injury, the patient presented with an infected lateral wound with purulent discharge. He was taken to the operating room for initial débridement, irrigation, and fracture stabilization with an antibiotic-coated plate and tension-band wiring of the medial malleoli. He was discharged from the hospital on day 4 after admission. Cultures of the wound grew beta-hemolytic strep group G and coagulase-negative staphylococci in broth that was sensitive to oxacillin, vancomycin, and gentamycin. The patient was treated with a 6-week regimen of Unasyn (Roerig, New York, New York), developed bony union, and has been free of clinical signs of infection for 2 years (Figures 3, 4).

Case 2

A 27-year-old male carpenter fell from a height of 12 feet and sustained a fracture of the distal radius that was treated with external fixation. The proximal pin site became clinically infected and subsequently developed osteomyelitis. The patient had a draining wound with a fracture for 2 months. He underwent débridement with partial resection of the radius and placement of an antibiotic cement–coated plate and calcium phosphate bone-void filler impregnated with antibiotics. Pathology specimens were positive for osteomyelitis, and bone cultures showed methicillin-sensitive Staphylococcus aureus (MSSA). He received intravenously administered antibiotic therapy for 6 weeks after surgery. The patient has remained free of clinical signs of infection for more than 1 year and has achieved bony union (Figures 5A, 5B).

Case 3

A 44-year-old woman with insulin-dependent diabetes mellitus and venous stasis sustained a trimalleolar ankle fracture after a low-energy fall that was initially treated with ORIF. She underwent revision ORIF to treat a malunion 3 months after initial treatment. At 8 months, the patient developed a draining sinus communicating with the plate. Computed tomography revealed nonunion and indicated infection. The patient underwent resection of the osteomyelitis and repair of the fibular nonunion with an antibiotic-coated plate. Tissue cultures were positive for coagulase-negative staphylococcus, and pathology specimens were positive for osteomyelitis. She received postoperative antibiotics intravenously and 6 weeks of antibiotic therapy after discharge from the hospital. The patient has remained free of clinical signs of infection for more than 1 year and has achieved bony union (Figures 6, 7).

Case 4

A 48-year-old man sustained an open olecranon fracture in another country. The fracture was initially treated with 1 dose of intravenously administered antibiotics and 5 days of orally administered antibiotics. The patient returned to the United States and was treated with intravenously administered antibiotics for cellulitis of the elbow for 11 days before referral to our institution, where he underwent ORIF with placement of an antibiotic-coated plate and tension-band wiring. Soft-tissue and bone cultures had no growth. He received intravenously administered antibiotics for 6 weeks. At 5 months postoperatively, the plate was removed because of pain. The patient has remained free of clinical signs of infection for more than 1 year and has achieved bony union (Figures 8A-8C).

Discussion

Acute infections of fractures have recently been treated with success by Berkes and colleagues,¹ who reported a 71% union rate achieved with operative débridement, antibiotic suppression, and retention of fixation until fracture union occurs. The study by Berkes and colleagues¹ had a small patient population, and larger cohorts are needed to show more reliable results; however, this treatment maintains structural support for the fracture during healing but requires multiple trips to the operating room for débridements as well as the use of systemic intravenous antibiotic therapy.

A technique that was developed by the primary author (Janet D. Conway, MD) and has not been described in the literature allows for use of antibiotic cement–coated plates to treat early postoperative infections and osteomyelitic nonunions. This approach permits fracture stabilization and local delivery of high concentrations of broad-spectrum antibiotics and can reduce the number of débridement procedures required in the operating room. We present a technique that includes the use of antibiotic cement–coated plates to treat early postoperative infections associated with fractures and nonunions in order to provide eradication of infection and bony stabilization.

Our approach parallels the current theory that treating infection at a site of union is preferable to treating infection at a site of nonunion.¹ Fixation devices should remain in place until osseous union is achieved. With the addition of antibiotics to the plate, removal might not be necessary unless a device is loose, nonfunctional, or, ultimately, causing pain. Other options, such as external fixation, can be burdensome to patients and can be associated with other risks. One of our 4 patients required fixation removal because of pain at the elbow; however, even noncoated olecranon plates typically are removed because of pain after fracture healing. Antibiotic cement adds bulk to the construct and can become very prominent in areas of little soft-tissue coverage (Figure 9).

Studies, assessing variables that correlate with higher likelihood of failure for primary repairs, have shown that open fracture, use of an intramedullary nail, and smoking are the highest risk factors for infected nonunion.¹⁻⁴ Among our 4 patients, 3 were smokers and 1 originally had an open fracture. Smokers have been found to have a 37% higher nonunion rate and are 2 times more likely to develop wound infection and osteomyelitis.^1,5 More than 60% of the time, infections are caused by S aureus or coagulase-negative staphylococci.^1,5,6 In our study population, 3 of the 4 patients had coagulase-negative staphylococci grow in the cultures. Implants infected with S aureus or Candida require surgical removal. Those with less virulent coagulase-negative staphylococci might not necessitate removal; however, our population had had antibiotic therapy and continued draining sinus.⁵ Rightmire and colleagues⁷ reported that those who develop infection earlier than 16 weeks postoperatively have a 68% success rate and that smoking is a major risk factor for infection. Development of Pseudomonas in the wound has been shown to have a positive correlation with amputation.^1,2 Infection with Pseudomonas, smoking, and involvement of the femur, tibia, ankle, or foot tended to result in failure.^1,2 Being clinically free of signs of infection after 3 months offers a 50% cure rate, with 78% at 6 months and 95% after 1 year.²

When determining an antibiotic to use with the polymethylmethacrylate (PMMA) cement, many factors must be considered, including spectrum, heat stability, and elution characteristics.⁸ A synergistic effect has been seen with combinations of antibiotics (eg, vancomycin and tobramycin used together). Vancomycin concentrations increased by 103% and tobramycin by 68% when used together compared with their elution rates when used alone, showing passive opportunism.⁹ This will, in essence, increase concentrations of antibiotics at the site locally, which will increase the bacteriocidal potential but also create a larger antimicrobial spectrum.⁹

The authors used Cobalt Bone Cement (Biomet Orthopedics, Inc, Warsaw, Indiana) which been shown to have higher elution properties than Simplex P Bone Cement (Stryker, Kalamazoo, Michigan).^3,10 The majority of elution occurs in the first 3 to 5 days but can continue for weeks after implantation. We place the cement on the plate allowing for its retention, hoping to eliminate a second surgery for removal.⁸ We recommend 3.6 g of tobramycin, and 1 g of vancomycin per 40-g bag of PMMA.³ This dose has been shown to be safe in respect to renal toxicity, plus the entire dose is not administered in a single setting because only a small portion of the cement is used when coating the plate. We close all wounds primarily, and do not regularly use drains or vacuum-assisted closures to help prevent a decrease in the local concentration of the antibiotics.¹¹

Broad-spectrum antibiotics are used to coat the plate in order to cover as many microbial organisms as possible without knowing the final offending organism. In our experience, this current technique provides antibiotic delivery with bony stability, therefore eliminating the need for multiple sequential surgical procedures. This difficult patient problem does not occur with enough frequency to warrant a large randomized clinical trial. However, this technique has been effective in these cases and may be useful to orthopedic surgeons in the future.

Conclusion

Based on our experience, early aggressive débridement, coupled with broad-spectrum antibiotic cement–coated plate insertion, provides fracture stability and helps eradicate the infection with 1 surgical procedure.

Deep infection in the presence of an implant after open reduction and internal fixation (ORIF) is usually treated with removal of the implant, serial débridement procedures, lavage, intravenously administered antibiotics, and, in some cases, placement of antibiotic-impregnated beads. If infection occurs during the early stages of bone healing, stabilization of the fractures might be compromised after removal of the implant. Although antibiotic-impregnated beads offer local delivery of antibiotics, they do not provide structural support of the fracture site. The beads often are difficult to remove after in-growth of granulation tissue. In areas of subcutaneous bone, an antibiotic bead pouch might be preferred to an open wound. Published research regarding the use of antibiotic-coated plates during the acute or chronic stages of infection is scarce. Plates offer the versatility of fracture stabilization, and the addition of antibiotic cement to the plates might aid in eradication of infection without necessitating a second surgery for removal. The patients provided written informed consent for print and electronic publication of these case reports.

Technique

After removal of implants, we perform débridement of the soft tissues with a hydroscalpel (Versajet; Smith & Nephew, London, United Kingdom), mechanical débridement of bone, and curettage with high speed burr. The wound is then irrigated with pulse pressure lavage and a minimum of 3 L sterile normal saline. The extremity is re-prepped and re-draped; the entire surgical team’s gowns and gloves are changed; and new instrumentation, including cautery and suction equipment, is used. The cement is prepared with tobramycin (3.6 g) and vancomycin (1 g) per 40-g bag of cement. The plate is placed in silicon tubing, and the antibiotic-prepared cement is injected into the tubing and molded until dry. Care is taken to mold the locations of the screw holes by making incisions in the tubing at the appropriate locations. Screws are placed through the screw holes to ensure locking capability, and Kirschner wires are placed through temporary fixation holes (Figure 1). Once dry, the screws and wires are removed from the plate, and the cement-coated plate is removed from the tubing. The antibiotic-coated plate is applied to the fracture or osteotomy site and is seated with screws as appropriate (Figure 2). The wound is closed primarily. Wound drains or vacuum-assisted closure devices are not routinely used unless there is high risk for hematoma formation. The authors prefer to have high local concentrations of antibiotic in the surrounding tissues and wound.

Clinical Series

Case 1

A 31-year-old man fell from a ladder and sustained a bimalleolar ankle fracture-dislocation that was treated with ORIF. Three weeks after initial injury, the patient presented with an infected lateral wound with purulent discharge. He was taken to the operating room for initial débridement, irrigation, and fracture stabilization with an antibiotic-coated plate and tension-band wiring of the medial malleoli. He was discharged from the hospital on day 4 after admission. Cultures of the wound grew beta-hemolytic strep group G and coagulase-negative staphylococci in broth that was sensitive to oxacillin, vancomycin, and gentamycin. The patient was treated with a 6-week regimen of Unasyn (Roerig, New York, New York), developed bony union, and has been free of clinical signs of infection for 2 years (Figures 3, 4).

Case 2

A 27-year-old male carpenter fell from a height of 12 feet and sustained a fracture of the distal radius that was treated with external fixation. The proximal pin site became clinically infected and subsequently developed osteomyelitis. The patient had a draining wound with a fracture for 2 months. He underwent débridement with partial resection of the radius and placement of an antibiotic cement–coated plate and calcium phosphate bone-void filler impregnated with antibiotics. Pathology specimens were positive for osteomyelitis, and bone cultures showed methicillin-sensitive Staphylococcus aureus (MSSA). He received intravenously administered antibiotic therapy for 6 weeks after surgery. The patient has remained free of clinical signs of infection for more than 1 year and has achieved bony union (Figures 5A, 5B).

Case 3

A 44-year-old woman with insulin-dependent diabetes mellitus and venous stasis sustained a trimalleolar ankle fracture after a low-energy fall that was initially treated with ORIF. She underwent revision ORIF to treat a malunion 3 months after initial treatment. At 8 months, the patient developed a draining sinus communicating with the plate. Computed tomography revealed nonunion and indicated infection. The patient underwent resection of the osteomyelitis and repair of the fibular nonunion with an antibiotic-coated plate. Tissue cultures were positive for coagulase-negative staphylococcus, and pathology specimens were positive for osteomyelitis. She received postoperative antibiotics intravenously and 6 weeks of antibiotic therapy after discharge from the hospital. The patient has remained free of clinical signs of infection for more than 1 year and has achieved bony union (Figures 6, 7).

Case 4

A 48-year-old man sustained an open olecranon fracture in another country. The fracture was initially treated with 1 dose of intravenously administered antibiotics and 5 days of orally administered antibiotics. The patient returned to the United States and was treated with intravenously administered antibiotics for cellulitis of the elbow for 11 days before referral to our institution, where he underwent ORIF with placement of an antibiotic-coated plate and tension-band wiring. Soft-tissue and bone cultures had no growth. He received intravenously administered antibiotics for 6 weeks. At 5 months postoperatively, the plate was removed because of pain. The patient has remained free of clinical signs of infection for more than 1 year and has achieved bony union (Figures 8A-8C).

Discussion

Acute infections of fractures have recently been treated with success by Berkes and colleagues,¹ who reported a 71% union rate achieved with operative débridement, antibiotic suppression, and retention of fixation until fracture union occurs. The study by Berkes and colleagues¹ had a small patient population, and larger cohorts are needed to show more reliable results; however, this treatment maintains structural support for the fracture during healing but requires multiple trips to the operating room for débridements as well as the use of systemic intravenous antibiotic therapy.

A technique that was developed by the primary author (Janet D. Conway, MD) and has not been described in the literature allows for use of antibiotic cement–coated plates to treat early postoperative infections and osteomyelitic nonunions. This approach permits fracture stabilization and local delivery of high concentrations of broad-spectrum antibiotics and can reduce the number of débridement procedures required in the operating room. We present a technique that includes the use of antibiotic cement–coated plates to treat early postoperative infections associated with fractures and nonunions in order to provide eradication of infection and bony stabilization.

Our approach parallels the current theory that treating infection at a site of union is preferable to treating infection at a site of nonunion.¹ Fixation devices should remain in place until osseous union is achieved. With the addition of antibiotics to the plate, removal might not be necessary unless a device is loose, nonfunctional, or, ultimately, causing pain. Other options, such as external fixation, can be burdensome to patients and can be associated with other risks. One of our 4 patients required fixation removal because of pain at the elbow; however, even noncoated olecranon plates typically are removed because of pain after fracture healing. Antibiotic cement adds bulk to the construct and can become very prominent in areas of little soft-tissue coverage (Figure 9).

Studies, assessing variables that correlate with higher likelihood of failure for primary repairs, have shown that open fracture, use of an intramedullary nail, and smoking are the highest risk factors for infected nonunion.¹⁻⁴ Among our 4 patients, 3 were smokers and 1 originally had an open fracture. Smokers have been found to have a 37% higher nonunion rate and are 2 times more likely to develop wound infection and osteomyelitis.^1,5 More than 60% of the time, infections are caused by S aureus or coagulase-negative staphylococci.^1,5,6 In our study population, 3 of the 4 patients had coagulase-negative staphylococci grow in the cultures. Implants infected with S aureus or Candida require surgical removal. Those with less virulent coagulase-negative staphylococci might not necessitate removal; however, our population had had antibiotic therapy and continued draining sinus.⁵ Rightmire and colleagues⁷ reported that those who develop infection earlier than 16 weeks postoperatively have a 68% success rate and that smoking is a major risk factor for infection. Development of Pseudomonas in the wound has been shown to have a positive correlation with amputation.^1,2 Infection with Pseudomonas, smoking, and involvement of the femur, tibia, ankle, or foot tended to result in failure.^1,2 Being clinically free of signs of infection after 3 months offers a 50% cure rate, with 78% at 6 months and 95% after 1 year.²

When determining an antibiotic to use with the polymethylmethacrylate (PMMA) cement, many factors must be considered, including spectrum, heat stability, and elution characteristics.⁸ A synergistic effect has been seen with combinations of antibiotics (eg, vancomycin and tobramycin used together). Vancomycin concentrations increased by 103% and tobramycin by 68% when used together compared with their elution rates when used alone, showing passive opportunism.⁹ This will, in essence, increase concentrations of antibiotics at the site locally, which will increase the bacteriocidal potential but also create a larger antimicrobial spectrum.⁹

The authors used Cobalt Bone Cement (Biomet Orthopedics, Inc, Warsaw, Indiana) which been shown to have higher elution properties than Simplex P Bone Cement (Stryker, Kalamazoo, Michigan).^3,10 The majority of elution occurs in the first 3 to 5 days but can continue for weeks after implantation. We place the cement on the plate allowing for its retention, hoping to eliminate a second surgery for removal.⁸ We recommend 3.6 g of tobramycin, and 1 g of vancomycin per 40-g bag of PMMA.³ This dose has been shown to be safe in respect to renal toxicity, plus the entire dose is not administered in a single setting because only a small portion of the cement is used when coating the plate. We close all wounds primarily, and do not regularly use drains or vacuum-assisted closures to help prevent a decrease in the local concentration of the antibiotics.¹¹

Broad-spectrum antibiotics are used to coat the plate in order to cover as many microbial organisms as possible without knowing the final offending organism. In our experience, this current technique provides antibiotic delivery with bony stability, therefore eliminating the need for multiple sequential surgical procedures. This difficult patient problem does not occur with enough frequency to warrant a large randomized clinical trial. However, this technique has been effective in these cases and may be useful to orthopedic surgeons in the future.

Conclusion

Based on our experience, early aggressive débridement, coupled with broad-spectrum antibiotic cement–coated plate insertion, provides fracture stability and helps eradicate the infection with 1 surgical procedure.

Intravesicular instillation of bacillus Calmette-Guérin (BCG), an attenuated form of Mycobacterium bovis, is the most effective treatment for superficial bladder cancer.^1,2 Minor local reactions to this treatment, such as cystitis and hematuria, are common, but more severe systemic complications^3,4 have also been documented, including sepsis, pneumonitis, granulomatous hepatitis, vertebral osteomyelitis,^5,6 and rarely, total joint infection.^7-11

We present a case of M bovis infection of a total knee arthroplasty (TKA) after BCG immunotherapy for bladder cancer that was successfully treated with antitubercular chemotherapy and retention of implants. We include a review of the literature addressing this rare mode of infection. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 66-year-old man presented with a chief complaint of progressive left knee stiffness over several months. Five years earlier, he underwent uncemented left TKA. His knee was functioning well with active range of motion from 0° to 126°, and he had returned to strenuous cycling. One year after his TKA and 4 years prior to the onset of stiffness, he had been diagnosed with superficial transitional cell carcinoma of the bladder. His treatment included intravesicular BCG therapy weekly for 6 weeks followed by semi-annual maintenance therapy. 

Initial examination upon presentation with left knee stiffness showed a significant effusion and diminished range of motion but little discomfort. The patient denied fever, chills, night sweats, and weight loss. Radiographs were normal with good component positioning and normal-appearing bone-implant interfaces (Figures A, B). Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and white blood cell count (WBC) were within normal limits, and aspirate of the knee revealed no organisms. Based on these findings, the presumptive diagnosis was an adverse reaction to polyethylene wear. Because of persistent stiffness, the patient underwent an examination under anesthesia, arthroscopy, and major synovectomy with biopsy. Intraoperative findings included normal polyethylene but a marked hypertrophic synovitis and abnormal, semi-turbid fluid. The fluid WBC count was 5.35×10⁹/L but no organisms were isolated initially. Histologic samples showed chronic inflammation with patches of acute inflammation. Approximately 6 weeks after surgery, cultures became positive for acid-fast bacillus, which was identified as M bovis. 

Maintenance BCG therapy was discontinued, and antitubercular chemotherapy was initiated, consisting of 12 months of rifampin 600 mg daily and isoniazid 300 mg daily. Because symptoms significantly improved after arthroscopic incision and drainage and synovectomy, the TKA implants were maintained and symptoms closely monitored. Subsequent cultures and biopsies remained negative, and the patient continued to do well clinically with no residual stiffness. 

At 7½-year follow-up, there is no clinical evidence of infection, and the patient continues to enjoy a high level of function with no pain and no recurrent stiffness. He has returned to cycling, logging more than 40,000 miles. However, a recurrence of bladder cancer is being treated with mitomycin C and gemcitabine, alternative to BCG.

Discussion

Mycobacterial infection in total joint arthroplasty (TJA) is uncommon;¹²M bovis infection of joint arthroplasty after intravesicular BCG therapy is exceedingly rare. Joint infection is thought to be the result of dissemination of BCG throughout the bloodstream.¹³ 

A review of the literature of BCG infection of TJA after intravesicular therapy for bladder cancer revealed only 5 case reports (Table). The average age on presentation was 77 years, and all patients were men, with 4 total hip arthroplasties (THAs) and 1 TKA. The average time from index procedure to initial presentation was 7.8 years, and the average time from cancer diagnosis to initial presentation was 20 months. Patients received an average of 8.6 consecutive weeks of BCG treatments, and maintenance therapy was not noted in any of the published reports. The average duration of antitubercular therapy was 13 months, and it comprised either 2- or 3-agent therapy. All reported cases were treated with removal of primary implants in either a 1- or 2-stage fashion. To our knowledge, this is only the second case of BCG infection of TKA reported in the literature and the first report of successful treatment with retention of primary implants. 

There are several possible explanations for the success of a more conservative treatment approach in our patient. First, this TKA was uncemented. Second, BCG is an attenuated form of M bovis, which is itself a relatively less virulent species than M tuberculosis. Finally, mycobacterial species do not produce the biofilm that is seen in other bacterial arthroplasty infections, which typically necessitate removal of implants in cases of chronic infection.¹⁴ 

This case was unique because the patient lacked signs of infectious symptoms, there were normal inflammatory markers, and arthroscopy was necessary to aid in the diagnosis. The definitive diagnosis in this case was significantly delayed to attain a positive M bovis culture. Definitive treatment was provided by arthroscopy, implant salvage, and antitubercular chemotherapy only. The standard of care for an infected modular TKA normally involves revision of the polyethylene tibial insert with irrigation and débridement, or removal of components and insertion of new implants in a 1- or 2-stage procedure. Despite the unusual algorithm to reach a definitive diagnosis of an infected joint arthroplasty in this case, we do not recommend arthroscopic biopsy, washout, and antimicrobial therapy as definitive treatment for infected joint arthroplasty, and we continue to support the removal of infected components in a staged manner.

Conclusion

Joint replacement patients with bladder cancer represent a relatively small cohort. Based on current demographics and the increasing demand for joint arthroplasty, it is likely that this unique subset of patients will grow. No current standard of care exists for the treatment of these patients. One preventative measure is to consider alternative types of chemotherapy for bladder cancer treatment, such as mitomycin. Another potential solution would be administration of prophylactic doses of antitubercular agents concomitantly with intravesicular BCG, which would allow for the local effects of BCG immunotherapy while controlling the potential for systemic dissemination. The optimal dose range to achieve this dual effect is not known and is an area for research. 

It is important for both arthroplasty surgeons and urologists to be aware of this potential complication in order to appropriately counsel this unique subset of patients. Our case report is the first to demonstrate that a successful outcome can be obtained with retention of primary components. Through research and continued data acquisition, a more concrete standard of care can be established. Until then, we recommend a collaborative approach between informed parties to devise a patient-specific plan of care. 

Intravesicular instillation of bacillus Calmette-Guérin (BCG), an attenuated form of Mycobacterium bovis, is the most effective treatment for superficial bladder cancer.^1,2 Minor local reactions to this treatment, such as cystitis and hematuria, are common, but more severe systemic complications^3,4 have also been documented, including sepsis, pneumonitis, granulomatous hepatitis, vertebral osteomyelitis,^5,6 and rarely, total joint infection.^7-11

We present a case of M bovis infection of a total knee arthroplasty (TKA) after BCG immunotherapy for bladder cancer that was successfully treated with antitubercular chemotherapy and retention of implants. We include a review of the literature addressing this rare mode of infection. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 66-year-old man presented with a chief complaint of progressive left knee stiffness over several months. Five years earlier, he underwent uncemented left TKA. His knee was functioning well with active range of motion from 0° to 126°, and he had returned to strenuous cycling. One year after his TKA and 4 years prior to the onset of stiffness, he had been diagnosed with superficial transitional cell carcinoma of the bladder. His treatment included intravesicular BCG therapy weekly for 6 weeks followed by semi-annual maintenance therapy. 

Initial examination upon presentation with left knee stiffness showed a significant effusion and diminished range of motion but little discomfort. The patient denied fever, chills, night sweats, and weight loss. Radiographs were normal with good component positioning and normal-appearing bone-implant interfaces (Figures A, B). Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and white blood cell count (WBC) were within normal limits, and aspirate of the knee revealed no organisms. Based on these findings, the presumptive diagnosis was an adverse reaction to polyethylene wear. Because of persistent stiffness, the patient underwent an examination under anesthesia, arthroscopy, and major synovectomy with biopsy. Intraoperative findings included normal polyethylene but a marked hypertrophic synovitis and abnormal, semi-turbid fluid. The fluid WBC count was 5.35×10⁹/L but no organisms were isolated initially. Histologic samples showed chronic inflammation with patches of acute inflammation. Approximately 6 weeks after surgery, cultures became positive for acid-fast bacillus, which was identified as M bovis. 

Maintenance BCG therapy was discontinued, and antitubercular chemotherapy was initiated, consisting of 12 months of rifampin 600 mg daily and isoniazid 300 mg daily. Because symptoms significantly improved after arthroscopic incision and drainage and synovectomy, the TKA implants were maintained and symptoms closely monitored. Subsequent cultures and biopsies remained negative, and the patient continued to do well clinically with no residual stiffness. 

At 7½-year follow-up, there is no clinical evidence of infection, and the patient continues to enjoy a high level of function with no pain and no recurrent stiffness. He has returned to cycling, logging more than 40,000 miles. However, a recurrence of bladder cancer is being treated with mitomycin C and gemcitabine, alternative to BCG.

Discussion

Mycobacterial infection in total joint arthroplasty (TJA) is uncommon;¹²M bovis infection of joint arthroplasty after intravesicular BCG therapy is exceedingly rare. Joint infection is thought to be the result of dissemination of BCG throughout the bloodstream.¹³ 

A review of the literature of BCG infection of TJA after intravesicular therapy for bladder cancer revealed only 5 case reports (Table). The average age on presentation was 77 years, and all patients were men, with 4 total hip arthroplasties (THAs) and 1 TKA. The average time from index procedure to initial presentation was 7.8 years, and the average time from cancer diagnosis to initial presentation was 20 months. Patients received an average of 8.6 consecutive weeks of BCG treatments, and maintenance therapy was not noted in any of the published reports. The average duration of antitubercular therapy was 13 months, and it comprised either 2- or 3-agent therapy. All reported cases were treated with removal of primary implants in either a 1- or 2-stage fashion. To our knowledge, this is only the second case of BCG infection of TKA reported in the literature and the first report of successful treatment with retention of primary implants. 

There are several possible explanations for the success of a more conservative treatment approach in our patient. First, this TKA was uncemented. Second, BCG is an attenuated form of M bovis, which is itself a relatively less virulent species than M tuberculosis. Finally, mycobacterial species do not produce the biofilm that is seen in other bacterial arthroplasty infections, which typically necessitate removal of implants in cases of chronic infection.¹⁴ 

This case was unique because the patient lacked signs of infectious symptoms, there were normal inflammatory markers, and arthroscopy was necessary to aid in the diagnosis. The definitive diagnosis in this case was significantly delayed to attain a positive M bovis culture. Definitive treatment was provided by arthroscopy, implant salvage, and antitubercular chemotherapy only. The standard of care for an infected modular TKA normally involves revision of the polyethylene tibial insert with irrigation and débridement, or removal of components and insertion of new implants in a 1- or 2-stage procedure. Despite the unusual algorithm to reach a definitive diagnosis of an infected joint arthroplasty in this case, we do not recommend arthroscopic biopsy, washout, and antimicrobial therapy as definitive treatment for infected joint arthroplasty, and we continue to support the removal of infected components in a staged manner.

Conclusion

Joint replacement patients with bladder cancer represent a relatively small cohort. Based on current demographics and the increasing demand for joint arthroplasty, it is likely that this unique subset of patients will grow. No current standard of care exists for the treatment of these patients. One preventative measure is to consider alternative types of chemotherapy for bladder cancer treatment, such as mitomycin. Another potential solution would be administration of prophylactic doses of antitubercular agents concomitantly with intravesicular BCG, which would allow for the local effects of BCG immunotherapy while controlling the potential for systemic dissemination. The optimal dose range to achieve this dual effect is not known and is an area for research. 

It is important for both arthroplasty surgeons and urologists to be aware of this potential complication in order to appropriately counsel this unique subset of patients. Our case report is the first to demonstrate that a successful outcome can be obtained with retention of primary components. Through research and continued data acquisition, a more concrete standard of care can be established. Until then, we recommend a collaborative approach between informed parties to devise a patient-specific plan of care. 

Intravesicular instillation of bacillus Calmette-Guérin (BCG), an attenuated form of Mycobacterium bovis, is the most effective treatment for superficial bladder cancer.^1,2 Minor local reactions to this treatment, such as cystitis and hematuria, are common, but more severe systemic complications^3,4 have also been documented, including sepsis, pneumonitis, granulomatous hepatitis, vertebral osteomyelitis,^5,6 and rarely, total joint infection.^7-11

We present a case of M bovis infection of a total knee arthroplasty (TKA) after BCG immunotherapy for bladder cancer that was successfully treated with antitubercular chemotherapy and retention of implants. We include a review of the literature addressing this rare mode of infection. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 66-year-old man presented with a chief complaint of progressive left knee stiffness over several months. Five years earlier, he underwent uncemented left TKA. His knee was functioning well with active range of motion from 0° to 126°, and he had returned to strenuous cycling. One year after his TKA and 4 years prior to the onset of stiffness, he had been diagnosed with superficial transitional cell carcinoma of the bladder. His treatment included intravesicular BCG therapy weekly for 6 weeks followed by semi-annual maintenance therapy. 

Initial examination upon presentation with left knee stiffness showed a significant effusion and diminished range of motion but little discomfort. The patient denied fever, chills, night sweats, and weight loss. Radiographs were normal with good component positioning and normal-appearing bone-implant interfaces (Figures A, B). Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and white blood cell count (WBC) were within normal limits, and aspirate of the knee revealed no organisms. Based on these findings, the presumptive diagnosis was an adverse reaction to polyethylene wear. Because of persistent stiffness, the patient underwent an examination under anesthesia, arthroscopy, and major synovectomy with biopsy. Intraoperative findings included normal polyethylene but a marked hypertrophic synovitis and abnormal, semi-turbid fluid. The fluid WBC count was 5.35×10⁹/L but no organisms were isolated initially. Histologic samples showed chronic inflammation with patches of acute inflammation. Approximately 6 weeks after surgery, cultures became positive for acid-fast bacillus, which was identified as M bovis. 

Maintenance BCG therapy was discontinued, and antitubercular chemotherapy was initiated, consisting of 12 months of rifampin 600 mg daily and isoniazid 300 mg daily. Because symptoms significantly improved after arthroscopic incision and drainage and synovectomy, the TKA implants were maintained and symptoms closely monitored. Subsequent cultures and biopsies remained negative, and the patient continued to do well clinically with no residual stiffness. 

At 7½-year follow-up, there is no clinical evidence of infection, and the patient continues to enjoy a high level of function with no pain and no recurrent stiffness. He has returned to cycling, logging more than 40,000 miles. However, a recurrence of bladder cancer is being treated with mitomycin C and gemcitabine, alternative to BCG.

Discussion

Mycobacterial infection in total joint arthroplasty (TJA) is uncommon;¹²M bovis infection of joint arthroplasty after intravesicular BCG therapy is exceedingly rare. Joint infection is thought to be the result of dissemination of BCG throughout the bloodstream.¹³ 

A review of the literature of BCG infection of TJA after intravesicular therapy for bladder cancer revealed only 5 case reports (Table). The average age on presentation was 77 years, and all patients were men, with 4 total hip arthroplasties (THAs) and 1 TKA. The average time from index procedure to initial presentation was 7.8 years, and the average time from cancer diagnosis to initial presentation was 20 months. Patients received an average of 8.6 consecutive weeks of BCG treatments, and maintenance therapy was not noted in any of the published reports. The average duration of antitubercular therapy was 13 months, and it comprised either 2- or 3-agent therapy. All reported cases were treated with removal of primary implants in either a 1- or 2-stage fashion. To our knowledge, this is only the second case of BCG infection of TKA reported in the literature and the first report of successful treatment with retention of primary implants. 

There are several possible explanations for the success of a more conservative treatment approach in our patient. First, this TKA was uncemented. Second, BCG is an attenuated form of M bovis, which is itself a relatively less virulent species than M tuberculosis. Finally, mycobacterial species do not produce the biofilm that is seen in other bacterial arthroplasty infections, which typically necessitate removal of implants in cases of chronic infection.¹⁴ 

This case was unique because the patient lacked signs of infectious symptoms, there were normal inflammatory markers, and arthroscopy was necessary to aid in the diagnosis. The definitive diagnosis in this case was significantly delayed to attain a positive M bovis culture. Definitive treatment was provided by arthroscopy, implant salvage, and antitubercular chemotherapy only. The standard of care for an infected modular TKA normally involves revision of the polyethylene tibial insert with irrigation and débridement, or removal of components and insertion of new implants in a 1- or 2-stage procedure. Despite the unusual algorithm to reach a definitive diagnosis of an infected joint arthroplasty in this case, we do not recommend arthroscopic biopsy, washout, and antimicrobial therapy as definitive treatment for infected joint arthroplasty, and we continue to support the removal of infected components in a staged manner.

Conclusion

Joint replacement patients with bladder cancer represent a relatively small cohort. Based on current demographics and the increasing demand for joint arthroplasty, it is likely that this unique subset of patients will grow. No current standard of care exists for the treatment of these patients. One preventative measure is to consider alternative types of chemotherapy for bladder cancer treatment, such as mitomycin. Another potential solution would be administration of prophylactic doses of antitubercular agents concomitantly with intravesicular BCG, which would allow for the local effects of BCG immunotherapy while controlling the potential for systemic dissemination. The optimal dose range to achieve this dual effect is not known and is an area for research. 

It is important for both arthroplasty surgeons and urologists to be aware of this potential complication in order to appropriately counsel this unique subset of patients. Our case report is the first to demonstrate that a successful outcome can be obtained with retention of primary components. Through research and continued data acquisition, a more concrete standard of care can be established. Until then, we recommend a collaborative approach between informed parties to devise a patient-specific plan of care. 

Surgical site infection after arthroplasty causes substantial morbidity and potential mortality. Prosthetic joint infection (PJI) ranges from simple superficial wound infection and cellulitis to deep subfascial infection that involves the prosthesis. Consistent use of prophylactic antibiotics has reduced postoperative hip and knee arthroplasty infections to rates of 0.25% to 2%.^1-4 Treatment of a patient with PJI commonly includes hospitalization, long-term intravenously administered antibiotics, resection arthroplasty, and staged reimplantation. The estimated cost of interventions reaches tens of millions of dollars annually in the United States and does not include the costs of psychosocial effects on patients and their families.^5,6

Betadine (povidone-iodine) is a widely used antiseptic for skin and mucous membrane wounds and has been shown to be effective for the prevention of PJI.⁷ Dilute Betadine solution has been proposed as an aid in treatment of PJI.⁸ At a minimum concentration of 5%, cytotoxicity has been observed in chicken tibia osteoblasts.⁹ A balance of the bactericidal and cytotoxic activities of Betadine, while maintaining its efficacy against resistant organisms, such as methicillin-resistant Staphylococcus aureus (MRSA), is optimized at dilutions between 0.5% and 4%.^10-14 We hypothesized that a dilute Betadine lavage of 3.5% would achieve a significant decrease in bacterial counts compared with an isolated saline lavage in an in vivo knee PJI model.

Materials and Methods

Animal Protocol

All surgical procedures were conducted according to the protocol approved by our institutional animal care and use committee. Using a power analysis and data obtained at our institution, we determined that 12 was the minimum number of animals needed to reach significance set at P < .05 and assuming a 50% decrease in colony-forming units (CFU) (SigmaStat Version 2.03; Aspire Software International, Ashburn, Virginia). Eight New Zealand White rabbits were used in our study; because significance was reached early, 12 were not needed. The average weight of the rabbits was 3.5 kg (weight range, 3.2-4.1 kg). All rabbits completed 1 week of acclimation before surgery.

Bacteria Preparation

A broth culture of methicillin-sensitive S aureus (MSSA) (ATCC 25923) was prepared 1 day before surgery. The bacteria were suspended in 5 mL of Trypticase Soy Broth (Becton Dickinson & Co, Franklin Lakes, New Jersey) and incubated at 37°C in a shaking incubator for 16 hours. The next day, the culture was centrifuged and irrigated twice with normal saline to remove the broth and prevent further growth. The bacteria were reconstituted in normal saline, and the concentration was standardized using a turbidity meter (LaMotte 2020e; LaMotte Co, Chestertown, Maryland), which correlated with 10⁶ CFU/100 µl plated on trypticase soy agar plates with 10% sheep blood (Fisher Scientific, Pittsburgh, Pennsylvania).

Surgical and Postoperative Procedures

Our procedure was based on the New Zealand White rabbit knee PJI model.¹⁵ General anesthesia was induced with ketamine and xylazine, and maintained with isoflurane inhalation via a nose cone mask. Rabbits were positioned supine, and bilateral knees were shaved, prepped, and draped in a sterile fashion.

A 2-cm longitudinal incision was made over the lateral knee, and arthrotomy was performed, exposing the lateral collateral ligament attachment at the lateral femoral condyle. Using a 4-mm drill bit, a defect was drilled obliquely into the lateral femoral condyle, anterior to the lateral collateral ligament attachment. This produced a defect in the non-weight-bearing, nonarticulating portion of the knee. A fully threaded 4×14-mm stainless steel screw (Synthes, West Chester, Pennsylvania) with a U-shaped ultrahigh-molecular-weight polyethylene washer (Synthes) was inserted into the defect. The joint capsule was closed with a running 3-0 Vicryl suture (Ethicon, Somerville, New Jersey). The knee joint was inoculated with 100 µL of the S aureus preparation using a 22-gauge needle. The skin was closed with a 4-0 Biosyn suture (Ethicon). The procedure was repeated on the contralateral knee (Figures 1A, 1B).

Seven days after the initial surgery, the rabbits were returned to the operating room and were anesthetized, positioned, and prepped for surgery as detailed above. Ceftriaxone (20 mg/kg of body weight) was intravenously administered to all rabbits for the treatment procedure. For each rabbit, a control knee and an experimental knee were randomly assigned. A longitudinal incision was made, exposing the previously placed implants. The screw was loosened slightly to remove the U-shaped polyethylene washer. Each knee then underwent lavage 2 times, for 90 seconds each time, with 3.5% dilute Betadine solution (experimental knee) or with normal saline (control knee). Because Pseudomonas contamination has been reported with povidone-iodine taken from unsterilized bottles,^16,17 packets of sterilized povidone-iodine (Aplicare; Clorox, Oakland, California) were used. After the irrigation was complete, a new sterile polyethylene washer was placed and the screw was tightened. The wound closure was repeated as detailed above.

Postoperative analgesia was provided based on a standard institutional animal care and use committee protocol. Rabbits were permitted full cage activity and nutrition ad libitum. Wound healing, body weight, and signs of distress were monitored daily.

Outcome Measures

Seven days after surgery, the rabbits were euthanized with administration of phenobarbital (100 mg/kg of body weight). Arterial blood samples were obtained from the auricular vein to ensure that the rabbits were not systemically infected. Using a sterile technique, the screw, polyethylene washer, lateral femoral condyle bone from the defect, and joint capsule were cultured. Harvested bone and soft tissues were weighed and immediately homogenized (PowerGen Model 35 Handheld Homogenizer; Thermo Fisher Scientific, Inc, Waltham, Massachusetts). Implants were sonicated (UBATH-Y; World Precision Instruments, Inc, Sarasota, Florida) in cold saline to obtain a sensitive culture.¹⁸

Bacterial quantification was determined by using trypticase soy agar plates after 24 hours of growth. Final CFU were calculated after serial dilutions and were standardized per gram of biopsied tissues.¹⁹ Members of the team were blinded to the treatment type.

Statistical Analysis

Statistical differences in mean bacterial burden were calculated independently for lateral condyle bone, joint capsule, polyethylene, and screws by conducting a Student t test.

Results

Treatment effect was higher than expected, and the study was terminated after 8 animals completed the protocol. All 8 rabbits tolerated the procedures well and were appropriately monitored during the postoperative period. No animals had signs of systemic infection or positive blood culture. All local cultures for screw, polyethylene washer, lateral femoral condyle defect, and joint capsule were positive.

Statistically significant decreases were shown in the bacterial burden of the Betadine-irrigated screws and the Betadine-irrigated polyethylene washers compared with the saline-irrigated controls. Betadine-irrigated screws grew an average of 7.16 × 10¹ CFU of S aureus/g, whereas screws from control knees grew an average of 1.45 × 10³ CFU/g (P = .0003) (Figure 2). Betadine-treated washers grew an average of 1.28 × 10³ CFU/g compared with 1.62 × 10⁴ CFU/g for control washers (P =. 04) (Figure 3).

A trend toward decreased bacterial counts was shown in Betadine-treated soft tissues compared with saline-treated soft tissues, but the difference did not reach statistical significance (P = .9). Biopsied joint capsule from knees treated with Betadine grew an average of 2.84 × 10⁴ CFU/g compared with an average of 3.16 × 10⁴ CFU/g in control-rabbit knees (Figure 4). Cultured lateral condyle from Betadine-treated knees had an average bacterial load of 3.22 × 10⁴ CFU/g compared with an average bacterial load of 1 × 10⁵ CFU/g in control knees (Figure 4).

Discussion

Knees irrigated with Betadine showed a significant (P = .0003) decrease in metal implant–related S aureus bacterial counts by 20-fold and a significant (P < .05) decrease in polyethylene implant–related counts by more than 10-fold. This arthroplasty model used Betadine lavage as a treatment adjunct with intravenously administered antibiotics and polyethylene exchange. Our 1-week interval after the index procedure classifies the infection as an acute postoperative arthroplasty infection (occurring less than 4 weeks postoperatively).

The gold standard treatment for these infections is irrigation and débridement with component retention.¹⁸ The success rate has been reported to be as high as 71%²⁰ but was closer to 44% in a study by Fridkin and colleagues,²¹ especially with more virulent bacteria. Staphylococcal species, higher American Society of Anesthesiologists scores, and frank pus around the prosthesis were markers of débridement failure in a recent study by Azzam and colleagues.¹⁸

The majority of postoperative joint arthroplasty infections are caused by S aureus, and the incidence of MRSA bacteria continues to rise.²² Community-acquired MRSA is increasing at an alarming rate and is now the predominant organism in skin and soft-tissue infections.²³ Organism resistance also occurs at a cellular level by the formation of a glycocalyx layer, or biofilm. This layer assists in changing the phenotypic properties of the organism and decreases the efficacy of antibiotics.²⁴ The self-produced layer of extracellular matrices, deoxyribonucleic acid, and polysaccharides attaches to inert material, preventing phagocytic action by neutrophils. In addition to antibacterial activity, povidone-iodine has antibiofilm activity against Staphylococcal species.²⁵ The active ingredient targets the gene that produces biofilm. This correlates to our study in which the largest decrease in bacterial counts was noted on the implants.

The use of Betadine lavage has shown some promise in vivo as well. A prospective randomized controlled trial²⁶ used 3.5% Betadine irrigation to prevent spine infection. No infections occurred in the Betadine group compared with a deep-infection rate of 2.9% in the control group. Brown and colleagues⁸ reviewed 1862 hip and knee arthroplasty cases before the use of Betadine lavage and 688 cases after the use of Betadine lavage and found a decrease in infection rate, from 0.97% to 0.15%. S aureus caused 13 of the 18 infections in the control group. These studies^8,26 used Betadine lavage for prophylaxis and prevention of deep spine and arthroplasty infection. Betadine lavage as a treatment adjunct for acute arthroplasty infection has not been studied clinically. It has the potential to increase isolated incision and débridement success and to improve component survivorship.

Our arthroplasty model mimics an intra-articular environment and accounts for an implant–polyethylene interface.¹⁵ Limitations of our study include the use of MSSA as opposed to MRSA. However, povidone-iodine has the same effects on both MSSA and MRSA.¹² We also treated our postoperative infection with 1 dose of antibiotics and not a course, although it should be noted that the single dose of ceftriaxone allowed us to isolate the independent effect of the Betadine lavage. A baseline level of infection severity could have been measured with cultures obtained at the time of irrigation and débridement. Also, a decrease in CFU does not directly correlate to a clinically significant outcome, such as a defined surgical site infection requiring intervention. Nevertheless, it is noteworthy that the decrease in bacterial counts on the stainless steel screws and polyethylene washers were maintained 1 week after the Betadine lavage.

Conclusion

Dilute Betadine lavage is a simple and inexpensive adjunct for the treatment of acute postoperative arthroplasty infection and may increase the rate of component retention. Additionally, the bactericidal and antibiofilm activities of Betadine may improve the effectiveness of systemic antibiotics. Further clinical investigation is warranted.

Surgical site infection after arthroplasty causes substantial morbidity and potential mortality. Prosthetic joint infection (PJI) ranges from simple superficial wound infection and cellulitis to deep subfascial infection that involves the prosthesis. Consistent use of prophylactic antibiotics has reduced postoperative hip and knee arthroplasty infections to rates of 0.25% to 2%.^1-4 Treatment of a patient with PJI commonly includes hospitalization, long-term intravenously administered antibiotics, resection arthroplasty, and staged reimplantation. The estimated cost of interventions reaches tens of millions of dollars annually in the United States and does not include the costs of psychosocial effects on patients and their families.^5,6

Betadine (povidone-iodine) is a widely used antiseptic for skin and mucous membrane wounds and has been shown to be effective for the prevention of PJI.⁷ Dilute Betadine solution has been proposed as an aid in treatment of PJI.⁸ At a minimum concentration of 5%, cytotoxicity has been observed in chicken tibia osteoblasts.⁹ A balance of the bactericidal and cytotoxic activities of Betadine, while maintaining its efficacy against resistant organisms, such as methicillin-resistant Staphylococcus aureus (MRSA), is optimized at dilutions between 0.5% and 4%.^10-14 We hypothesized that a dilute Betadine lavage of 3.5% would achieve a significant decrease in bacterial counts compared with an isolated saline lavage in an in vivo knee PJI model.

Materials and Methods

Animal Protocol

All surgical procedures were conducted according to the protocol approved by our institutional animal care and use committee. Using a power analysis and data obtained at our institution, we determined that 12 was the minimum number of animals needed to reach significance set at P < .05 and assuming a 50% decrease in colony-forming units (CFU) (SigmaStat Version 2.03; Aspire Software International, Ashburn, Virginia). Eight New Zealand White rabbits were used in our study; because significance was reached early, 12 were not needed. The average weight of the rabbits was 3.5 kg (weight range, 3.2-4.1 kg). All rabbits completed 1 week of acclimation before surgery.

Bacteria Preparation

A broth culture of methicillin-sensitive S aureus (MSSA) (ATCC 25923) was prepared 1 day before surgery. The bacteria were suspended in 5 mL of Trypticase Soy Broth (Becton Dickinson & Co, Franklin Lakes, New Jersey) and incubated at 37°C in a shaking incubator for 16 hours. The next day, the culture was centrifuged and irrigated twice with normal saline to remove the broth and prevent further growth. The bacteria were reconstituted in normal saline, and the concentration was standardized using a turbidity meter (LaMotte 2020e; LaMotte Co, Chestertown, Maryland), which correlated with 10⁶ CFU/100 µl plated on trypticase soy agar plates with 10% sheep blood (Fisher Scientific, Pittsburgh, Pennsylvania).

Surgical and Postoperative Procedures

Our procedure was based on the New Zealand White rabbit knee PJI model.¹⁵ General anesthesia was induced with ketamine and xylazine, and maintained with isoflurane inhalation via a nose cone mask. Rabbits were positioned supine, and bilateral knees were shaved, prepped, and draped in a sterile fashion.

A 2-cm longitudinal incision was made over the lateral knee, and arthrotomy was performed, exposing the lateral collateral ligament attachment at the lateral femoral condyle. Using a 4-mm drill bit, a defect was drilled obliquely into the lateral femoral condyle, anterior to the lateral collateral ligament attachment. This produced a defect in the non-weight-bearing, nonarticulating portion of the knee. A fully threaded 4×14-mm stainless steel screw (Synthes, West Chester, Pennsylvania) with a U-shaped ultrahigh-molecular-weight polyethylene washer (Synthes) was inserted into the defect. The joint capsule was closed with a running 3-0 Vicryl suture (Ethicon, Somerville, New Jersey). The knee joint was inoculated with 100 µL of the S aureus preparation using a 22-gauge needle. The skin was closed with a 4-0 Biosyn suture (Ethicon). The procedure was repeated on the contralateral knee (Figures 1A, 1B).

Seven days after the initial surgery, the rabbits were returned to the operating room and were anesthetized, positioned, and prepped for surgery as detailed above. Ceftriaxone (20 mg/kg of body weight) was intravenously administered to all rabbits for the treatment procedure. For each rabbit, a control knee and an experimental knee were randomly assigned. A longitudinal incision was made, exposing the previously placed implants. The screw was loosened slightly to remove the U-shaped polyethylene washer. Each knee then underwent lavage 2 times, for 90 seconds each time, with 3.5% dilute Betadine solution (experimental knee) or with normal saline (control knee). Because Pseudomonas contamination has been reported with povidone-iodine taken from unsterilized bottles,^16,17 packets of sterilized povidone-iodine (Aplicare; Clorox, Oakland, California) were used. After the irrigation was complete, a new sterile polyethylene washer was placed and the screw was tightened. The wound closure was repeated as detailed above.

Postoperative analgesia was provided based on a standard institutional animal care and use committee protocol. Rabbits were permitted full cage activity and nutrition ad libitum. Wound healing, body weight, and signs of distress were monitored daily.

Outcome Measures

Seven days after surgery, the rabbits were euthanized with administration of phenobarbital (100 mg/kg of body weight). Arterial blood samples were obtained from the auricular vein to ensure that the rabbits were not systemically infected. Using a sterile technique, the screw, polyethylene washer, lateral femoral condyle bone from the defect, and joint capsule were cultured. Harvested bone and soft tissues were weighed and immediately homogenized (PowerGen Model 35 Handheld Homogenizer; Thermo Fisher Scientific, Inc, Waltham, Massachusetts). Implants were sonicated (UBATH-Y; World Precision Instruments, Inc, Sarasota, Florida) in cold saline to obtain a sensitive culture.¹⁸

Bacterial quantification was determined by using trypticase soy agar plates after 24 hours of growth. Final CFU were calculated after serial dilutions and were standardized per gram of biopsied tissues.¹⁹ Members of the team were blinded to the treatment type.

Statistical Analysis

Statistical differences in mean bacterial burden were calculated independently for lateral condyle bone, joint capsule, polyethylene, and screws by conducting a Student t test.

Results

Treatment effect was higher than expected, and the study was terminated after 8 animals completed the protocol. All 8 rabbits tolerated the procedures well and were appropriately monitored during the postoperative period. No animals had signs of systemic infection or positive blood culture. All local cultures for screw, polyethylene washer, lateral femoral condyle defect, and joint capsule were positive.

Statistically significant decreases were shown in the bacterial burden of the Betadine-irrigated screws and the Betadine-irrigated polyethylene washers compared with the saline-irrigated controls. Betadine-irrigated screws grew an average of 7.16 × 10¹ CFU of S aureus/g, whereas screws from control knees grew an average of 1.45 × 10³ CFU/g (P = .0003) (Figure 2). Betadine-treated washers grew an average of 1.28 × 10³ CFU/g compared with 1.62 × 10⁴ CFU/g for control washers (P =. 04) (Figure 3).

A trend toward decreased bacterial counts was shown in Betadine-treated soft tissues compared with saline-treated soft tissues, but the difference did not reach statistical significance (P = .9). Biopsied joint capsule from knees treated with Betadine grew an average of 2.84 × 10⁴ CFU/g compared with an average of 3.16 × 10⁴ CFU/g in control-rabbit knees (Figure 4). Cultured lateral condyle from Betadine-treated knees had an average bacterial load of 3.22 × 10⁴ CFU/g compared with an average bacterial load of 1 × 10⁵ CFU/g in control knees (Figure 4).

Discussion

Knees irrigated with Betadine showed a significant (P = .0003) decrease in metal implant–related S aureus bacterial counts by 20-fold and a significant (P < .05) decrease in polyethylene implant–related counts by more than 10-fold. This arthroplasty model used Betadine lavage as a treatment adjunct with intravenously administered antibiotics and polyethylene exchange. Our 1-week interval after the index procedure classifies the infection as an acute postoperative arthroplasty infection (occurring less than 4 weeks postoperatively).

The gold standard treatment for these infections is irrigation and débridement with component retention.¹⁸ The success rate has been reported to be as high as 71%²⁰ but was closer to 44% in a study by Fridkin and colleagues,²¹ especially with more virulent bacteria. Staphylococcal species, higher American Society of Anesthesiologists scores, and frank pus around the prosthesis were markers of débridement failure in a recent study by Azzam and colleagues.¹⁸

The majority of postoperative joint arthroplasty infections are caused by S aureus, and the incidence of MRSA bacteria continues to rise.²² Community-acquired MRSA is increasing at an alarming rate and is now the predominant organism in skin and soft-tissue infections.²³ Organism resistance also occurs at a cellular level by the formation of a glycocalyx layer, or biofilm. This layer assists in changing the phenotypic properties of the organism and decreases the efficacy of antibiotics.²⁴ The self-produced layer of extracellular matrices, deoxyribonucleic acid, and polysaccharides attaches to inert material, preventing phagocytic action by neutrophils. In addition to antibacterial activity, povidone-iodine has antibiofilm activity against Staphylococcal species.²⁵ The active ingredient targets the gene that produces biofilm. This correlates to our study in which the largest decrease in bacterial counts was noted on the implants.

The use of Betadine lavage has shown some promise in vivo as well. A prospective randomized controlled trial²⁶ used 3.5% Betadine irrigation to prevent spine infection. No infections occurred in the Betadine group compared with a deep-infection rate of 2.9% in the control group. Brown and colleagues⁸ reviewed 1862 hip and knee arthroplasty cases before the use of Betadine lavage and 688 cases after the use of Betadine lavage and found a decrease in infection rate, from 0.97% to 0.15%. S aureus caused 13 of the 18 infections in the control group. These studies^8,26 used Betadine lavage for prophylaxis and prevention of deep spine and arthroplasty infection. Betadine lavage as a treatment adjunct for acute arthroplasty infection has not been studied clinically. It has the potential to increase isolated incision and débridement success and to improve component survivorship.

Our arthroplasty model mimics an intra-articular environment and accounts for an implant–polyethylene interface.¹⁵ Limitations of our study include the use of MSSA as opposed to MRSA. However, povidone-iodine has the same effects on both MSSA and MRSA.¹² We also treated our postoperative infection with 1 dose of antibiotics and not a course, although it should be noted that the single dose of ceftriaxone allowed us to isolate the independent effect of the Betadine lavage. A baseline level of infection severity could have been measured with cultures obtained at the time of irrigation and débridement. Also, a decrease in CFU does not directly correlate to a clinically significant outcome, such as a defined surgical site infection requiring intervention. Nevertheless, it is noteworthy that the decrease in bacterial counts on the stainless steel screws and polyethylene washers were maintained 1 week after the Betadine lavage.

Conclusion

Dilute Betadine lavage is a simple and inexpensive adjunct for the treatment of acute postoperative arthroplasty infection and may increase the rate of component retention. Additionally, the bactericidal and antibiofilm activities of Betadine may improve the effectiveness of systemic antibiotics. Further clinical investigation is warranted.

Surgical site infection after arthroplasty causes substantial morbidity and potential mortality. Prosthetic joint infection (PJI) ranges from simple superficial wound infection and cellulitis to deep subfascial infection that involves the prosthesis. Consistent use of prophylactic antibiotics has reduced postoperative hip and knee arthroplasty infections to rates of 0.25% to 2%.^1-4 Treatment of a patient with PJI commonly includes hospitalization, long-term intravenously administered antibiotics, resection arthroplasty, and staged reimplantation. The estimated cost of interventions reaches tens of millions of dollars annually in the United States and does not include the costs of psychosocial effects on patients and their families.^5,6

Betadine (povidone-iodine) is a widely used antiseptic for skin and mucous membrane wounds and has been shown to be effective for the prevention of PJI.⁷ Dilute Betadine solution has been proposed as an aid in treatment of PJI.⁸ At a minimum concentration of 5%, cytotoxicity has been observed in chicken tibia osteoblasts.⁹ A balance of the bactericidal and cytotoxic activities of Betadine, while maintaining its efficacy against resistant organisms, such as methicillin-resistant Staphylococcus aureus (MRSA), is optimized at dilutions between 0.5% and 4%.^10-14 We hypothesized that a dilute Betadine lavage of 3.5% would achieve a significant decrease in bacterial counts compared with an isolated saline lavage in an in vivo knee PJI model.

Materials and Methods

Animal Protocol

All surgical procedures were conducted according to the protocol approved by our institutional animal care and use committee. Using a power analysis and data obtained at our institution, we determined that 12 was the minimum number of animals needed to reach significance set at P < .05 and assuming a 50% decrease in colony-forming units (CFU) (SigmaStat Version 2.03; Aspire Software International, Ashburn, Virginia). Eight New Zealand White rabbits were used in our study; because significance was reached early, 12 were not needed. The average weight of the rabbits was 3.5 kg (weight range, 3.2-4.1 kg). All rabbits completed 1 week of acclimation before surgery.

Bacteria Preparation

A broth culture of methicillin-sensitive S aureus (MSSA) (ATCC 25923) was prepared 1 day before surgery. The bacteria were suspended in 5 mL of Trypticase Soy Broth (Becton Dickinson & Co, Franklin Lakes, New Jersey) and incubated at 37°C in a shaking incubator for 16 hours. The next day, the culture was centrifuged and irrigated twice with normal saline to remove the broth and prevent further growth. The bacteria were reconstituted in normal saline, and the concentration was standardized using a turbidity meter (LaMotte 2020e; LaMotte Co, Chestertown, Maryland), which correlated with 10⁶ CFU/100 µl plated on trypticase soy agar plates with 10% sheep blood (Fisher Scientific, Pittsburgh, Pennsylvania).

Surgical and Postoperative Procedures

Our procedure was based on the New Zealand White rabbit knee PJI model.¹⁵ General anesthesia was induced with ketamine and xylazine, and maintained with isoflurane inhalation via a nose cone mask. Rabbits were positioned supine, and bilateral knees were shaved, prepped, and draped in a sterile fashion.

A 2-cm longitudinal incision was made over the lateral knee, and arthrotomy was performed, exposing the lateral collateral ligament attachment at the lateral femoral condyle. Using a 4-mm drill bit, a defect was drilled obliquely into the lateral femoral condyle, anterior to the lateral collateral ligament attachment. This produced a defect in the non-weight-bearing, nonarticulating portion of the knee. A fully threaded 4×14-mm stainless steel screw (Synthes, West Chester, Pennsylvania) with a U-shaped ultrahigh-molecular-weight polyethylene washer (Synthes) was inserted into the defect. The joint capsule was closed with a running 3-0 Vicryl suture (Ethicon, Somerville, New Jersey). The knee joint was inoculated with 100 µL of the S aureus preparation using a 22-gauge needle. The skin was closed with a 4-0 Biosyn suture (Ethicon). The procedure was repeated on the contralateral knee (Figures 1A, 1B).

Seven days after the initial surgery, the rabbits were returned to the operating room and were anesthetized, positioned, and prepped for surgery as detailed above. Ceftriaxone (20 mg/kg of body weight) was intravenously administered to all rabbits for the treatment procedure. For each rabbit, a control knee and an experimental knee were randomly assigned. A longitudinal incision was made, exposing the previously placed implants. The screw was loosened slightly to remove the U-shaped polyethylene washer. Each knee then underwent lavage 2 times, for 90 seconds each time, with 3.5% dilute Betadine solution (experimental knee) or with normal saline (control knee). Because Pseudomonas contamination has been reported with povidone-iodine taken from unsterilized bottles,^16,17 packets of sterilized povidone-iodine (Aplicare; Clorox, Oakland, California) were used. After the irrigation was complete, a new sterile polyethylene washer was placed and the screw was tightened. The wound closure was repeated as detailed above.

Postoperative analgesia was provided based on a standard institutional animal care and use committee protocol. Rabbits were permitted full cage activity and nutrition ad libitum. Wound healing, body weight, and signs of distress were monitored daily.

Outcome Measures

Seven days after surgery, the rabbits were euthanized with administration of phenobarbital (100 mg/kg of body weight). Arterial blood samples were obtained from the auricular vein to ensure that the rabbits were not systemically infected. Using a sterile technique, the screw, polyethylene washer, lateral femoral condyle bone from the defect, and joint capsule were cultured. Harvested bone and soft tissues were weighed and immediately homogenized (PowerGen Model 35 Handheld Homogenizer; Thermo Fisher Scientific, Inc, Waltham, Massachusetts). Implants were sonicated (UBATH-Y; World Precision Instruments, Inc, Sarasota, Florida) in cold saline to obtain a sensitive culture.¹⁸

Bacterial quantification was determined by using trypticase soy agar plates after 24 hours of growth. Final CFU were calculated after serial dilutions and were standardized per gram of biopsied tissues.¹⁹ Members of the team were blinded to the treatment type.

Statistical Analysis

Statistical differences in mean bacterial burden were calculated independently for lateral condyle bone, joint capsule, polyethylene, and screws by conducting a Student t test.

Results

Treatment effect was higher than expected, and the study was terminated after 8 animals completed the protocol. All 8 rabbits tolerated the procedures well and were appropriately monitored during the postoperative period. No animals had signs of systemic infection or positive blood culture. All local cultures for screw, polyethylene washer, lateral femoral condyle defect, and joint capsule were positive.

Statistically significant decreases were shown in the bacterial burden of the Betadine-irrigated screws and the Betadine-irrigated polyethylene washers compared with the saline-irrigated controls. Betadine-irrigated screws grew an average of 7.16 × 10¹ CFU of S aureus/g, whereas screws from control knees grew an average of 1.45 × 10³ CFU/g (P = .0003) (Figure 2). Betadine-treated washers grew an average of 1.28 × 10³ CFU/g compared with 1.62 × 10⁴ CFU/g for control washers (P =. 04) (Figure 3).

A trend toward decreased bacterial counts was shown in Betadine-treated soft tissues compared with saline-treated soft tissues, but the difference did not reach statistical significance (P = .9). Biopsied joint capsule from knees treated with Betadine grew an average of 2.84 × 10⁴ CFU/g compared with an average of 3.16 × 10⁴ CFU/g in control-rabbit knees (Figure 4). Cultured lateral condyle from Betadine-treated knees had an average bacterial load of 3.22 × 10⁴ CFU/g compared with an average bacterial load of 1 × 10⁵ CFU/g in control knees (Figure 4).

Discussion

Knees irrigated with Betadine showed a significant (P = .0003) decrease in metal implant–related S aureus bacterial counts by 20-fold and a significant (P < .05) decrease in polyethylene implant–related counts by more than 10-fold. This arthroplasty model used Betadine lavage as a treatment adjunct with intravenously administered antibiotics and polyethylene exchange. Our 1-week interval after the index procedure classifies the infection as an acute postoperative arthroplasty infection (occurring less than 4 weeks postoperatively).

The gold standard treatment for these infections is irrigation and débridement with component retention.¹⁸ The success rate has been reported to be as high as 71%²⁰ but was closer to 44% in a study by Fridkin and colleagues,²¹ especially with more virulent bacteria. Staphylococcal species, higher American Society of Anesthesiologists scores, and frank pus around the prosthesis were markers of débridement failure in a recent study by Azzam and colleagues.¹⁸

The majority of postoperative joint arthroplasty infections are caused by S aureus, and the incidence of MRSA bacteria continues to rise.²² Community-acquired MRSA is increasing at an alarming rate and is now the predominant organism in skin and soft-tissue infections.²³ Organism resistance also occurs at a cellular level by the formation of a glycocalyx layer, or biofilm. This layer assists in changing the phenotypic properties of the organism and decreases the efficacy of antibiotics.²⁴ The self-produced layer of extracellular matrices, deoxyribonucleic acid, and polysaccharides attaches to inert material, preventing phagocytic action by neutrophils. In addition to antibacterial activity, povidone-iodine has antibiofilm activity against Staphylococcal species.²⁵ The active ingredient targets the gene that produces biofilm. This correlates to our study in which the largest decrease in bacterial counts was noted on the implants.

The use of Betadine lavage has shown some promise in vivo as well. A prospective randomized controlled trial²⁶ used 3.5% Betadine irrigation to prevent spine infection. No infections occurred in the Betadine group compared with a deep-infection rate of 2.9% in the control group. Brown and colleagues⁸ reviewed 1862 hip and knee arthroplasty cases before the use of Betadine lavage and 688 cases after the use of Betadine lavage and found a decrease in infection rate, from 0.97% to 0.15%. S aureus caused 13 of the 18 infections in the control group. These studies^8,26 used Betadine lavage for prophylaxis and prevention of deep spine and arthroplasty infection. Betadine lavage as a treatment adjunct for acute arthroplasty infection has not been studied clinically. It has the potential to increase isolated incision and débridement success and to improve component survivorship.

Our arthroplasty model mimics an intra-articular environment and accounts for an implant–polyethylene interface.¹⁵ Limitations of our study include the use of MSSA as opposed to MRSA. However, povidone-iodine has the same effects on both MSSA and MRSA.¹² We also treated our postoperative infection with 1 dose of antibiotics and not a course, although it should be noted that the single dose of ceftriaxone allowed us to isolate the independent effect of the Betadine lavage. A baseline level of infection severity could have been measured with cultures obtained at the time of irrigation and débridement. Also, a decrease in CFU does not directly correlate to a clinically significant outcome, such as a defined surgical site infection requiring intervention. Nevertheless, it is noteworthy that the decrease in bacterial counts on the stainless steel screws and polyethylene washers were maintained 1 week after the Betadine lavage.

Conclusion

Dilute Betadine lavage is a simple and inexpensive adjunct for the treatment of acute postoperative arthroplasty infection and may increase the rate of component retention. Additionally, the bactericidal and antibiofilm activities of Betadine may improve the effectiveness of systemic antibiotics. Further clinical investigation is warranted.

The JAK1/2 inhibitor ruxolitinib can outperform standard therapy in patients with polycythemia vera (PV), results of the RESPONSE trial suggest.

In patients who could not tolerate or were resistant to hydroxyurea, ruxolitinib proved superior to standard therapy for controlling hematocrit levels and reducing spleen volume

“This study indicates that ruxolitinib may represent an important advance for this population of patients with PV,” said Alessandro M. Vannucchi, MD, of the University of Florence in Italy.

Dr Vannucchi and his colleagues reported these findings in NEJM. The trial was funded by Incyte Corporation, the company developing ruxolitinib.

The phase 3 study included 222 patients. They were phlebotomy-dependent, had splenomegaly, and could not tolerate or were resistant to hydroxyurea.

The patients were randomized 1:1 to receive either ruxolitinib (starting dose of 10 mg twice daily) or standard therapy, which was defined as investigator-selected monotherapy or observation only. The ruxolitinib dose was adjusted as needed throughout the study.

The primary endpoint was a composite of hematocrit control and spleen reduction. To meet the endpoint, patients had to experience a 35% or greater reduction in spleen volume from baseline, as assessed by imaging at week 32.

And a patient’s hematocrit was considered under control if he was not eligible for phlebotomy from week 8 through 32 (and had no more than one instance of phlebotomy eligibility between randomization and week 8). Patients who were deemed eligible for phlebotomy had hematocrit that was greater than 45% or had increased 3 or more percentage points from the time they entered the study.

So 21% of patients in the ruxolitinib group met the primary endpoint, achieving both hematocrit control and spleen reduction. But only 1% of patients in the standard-therapy group did the same (P<0.001).

In all, 60% of patients in the ruxolitinib arm achieved hematocrit control, compared to 20% of those receiving standard therapy. And 38% of patients in the ruxolitinib arm had at least a 35% spleen reduction, compared to 1% of patients in the standard-therapy arm.

The rate of complete hematologic remission was significantly higher in the ruxolitinib group than in the standard-therapy group, at 24% and 9%, respectively (P=0.003).

And ruxolitinib-treated patients had a greater reduction in overall symptoms. Forty-nine percent of ruxolitinib-treated patients had at least a 50% reduction in their total symptom score at week 32 (as measured by the MPN-SAF 14-item total symptom score), compared to 5% of patients on standard therapy.

Based on these results, most patients in the standard-therapy arm crossed over to receive ruxolitinib immediately after week 32. So the researchers could only compare rates of adverse events through week 32.

They found that grade 3/4 anemia was more common with ruxolitinib than with standard therapy (2% and 0%, respectively). The same was true of grade 3/4 thrombocytopenia (5% and 4%, respectively) and herpes zoster infections of all grades (6% and 0%, respectively).

However, thromboembolic events were more common with standard therapy. They occurred in 6 patients who received standard therapy and 1 ruxolitinib-treated patient.

The most common non-hematologic adverse events in the ruxolitinib arm were headache (16%), diarrhea (15%), and fatigue (15%), which were mainly grade 1 or 2. The rates of these events in the standard therapy arm were 19%, 7%, and 15%, respectively.

The researchers also noted that nearly 85% of patients randomized to ruxolitinib were still receiving treatment at a median follow-up of 81 weeks.

The JAK1/2 inhibitor ruxolitinib can outperform standard therapy in patients with polycythemia vera (PV), results of the RESPONSE trial suggest.

In patients who could not tolerate or were resistant to hydroxyurea, ruxolitinib proved superior to standard therapy for controlling hematocrit levels and reducing spleen volume

“This study indicates that ruxolitinib may represent an important advance for this population of patients with PV,” said Alessandro M. Vannucchi, MD, of the University of Florence in Italy.

Dr Vannucchi and his colleagues reported these findings in NEJM. The trial was funded by Incyte Corporation, the company developing ruxolitinib.

The phase 3 study included 222 patients. They were phlebotomy-dependent, had splenomegaly, and could not tolerate or were resistant to hydroxyurea.

The patients were randomized 1:1 to receive either ruxolitinib (starting dose of 10 mg twice daily) or standard therapy, which was defined as investigator-selected monotherapy or observation only. The ruxolitinib dose was adjusted as needed throughout the study.

The primary endpoint was a composite of hematocrit control and spleen reduction. To meet the endpoint, patients had to experience a 35% or greater reduction in spleen volume from baseline, as assessed by imaging at week 32.

And a patient’s hematocrit was considered under control if he was not eligible for phlebotomy from week 8 through 32 (and had no more than one instance of phlebotomy eligibility between randomization and week 8). Patients who were deemed eligible for phlebotomy had hematocrit that was greater than 45% or had increased 3 or more percentage points from the time they entered the study.

So 21% of patients in the ruxolitinib group met the primary endpoint, achieving both hematocrit control and spleen reduction. But only 1% of patients in the standard-therapy group did the same (P<0.001).

In all, 60% of patients in the ruxolitinib arm achieved hematocrit control, compared to 20% of those receiving standard therapy. And 38% of patients in the ruxolitinib arm had at least a 35% spleen reduction, compared to 1% of patients in the standard-therapy arm.

The rate of complete hematologic remission was significantly higher in the ruxolitinib group than in the standard-therapy group, at 24% and 9%, respectively (P=0.003).

And ruxolitinib-treated patients had a greater reduction in overall symptoms. Forty-nine percent of ruxolitinib-treated patients had at least a 50% reduction in their total symptom score at week 32 (as measured by the MPN-SAF 14-item total symptom score), compared to 5% of patients on standard therapy.

Based on these results, most patients in the standard-therapy arm crossed over to receive ruxolitinib immediately after week 32. So the researchers could only compare rates of adverse events through week 32.

They found that grade 3/4 anemia was more common with ruxolitinib than with standard therapy (2% and 0%, respectively). The same was true of grade 3/4 thrombocytopenia (5% and 4%, respectively) and herpes zoster infections of all grades (6% and 0%, respectively).

However, thromboembolic events were more common with standard therapy. They occurred in 6 patients who received standard therapy and 1 ruxolitinib-treated patient.

The most common non-hematologic adverse events in the ruxolitinib arm were headache (16%), diarrhea (15%), and fatigue (15%), which were mainly grade 1 or 2. The rates of these events in the standard therapy arm were 19%, 7%, and 15%, respectively.

The researchers also noted that nearly 85% of patients randomized to ruxolitinib were still receiving treatment at a median follow-up of 81 weeks.

The JAK1/2 inhibitor ruxolitinib can outperform standard therapy in patients with polycythemia vera (PV), results of the RESPONSE trial suggest.

In patients who could not tolerate or were resistant to hydroxyurea, ruxolitinib proved superior to standard therapy for controlling hematocrit levels and reducing spleen volume

“This study indicates that ruxolitinib may represent an important advance for this population of patients with PV,” said Alessandro M. Vannucchi, MD, of the University of Florence in Italy.

Dr Vannucchi and his colleagues reported these findings in NEJM. The trial was funded by Incyte Corporation, the company developing ruxolitinib.

The phase 3 study included 222 patients. They were phlebotomy-dependent, had splenomegaly, and could not tolerate or were resistant to hydroxyurea.

The patients were randomized 1:1 to receive either ruxolitinib (starting dose of 10 mg twice daily) or standard therapy, which was defined as investigator-selected monotherapy or observation only. The ruxolitinib dose was adjusted as needed throughout the study.

The primary endpoint was a composite of hematocrit control and spleen reduction. To meet the endpoint, patients had to experience a 35% or greater reduction in spleen volume from baseline, as assessed by imaging at week 32.

And a patient’s hematocrit was considered under control if he was not eligible for phlebotomy from week 8 through 32 (and had no more than one instance of phlebotomy eligibility between randomization and week 8). Patients who were deemed eligible for phlebotomy had hematocrit that was greater than 45% or had increased 3 or more percentage points from the time they entered the study.

So 21% of patients in the ruxolitinib group met the primary endpoint, achieving both hematocrit control and spleen reduction. But only 1% of patients in the standard-therapy group did the same (P<0.001).

In all, 60% of patients in the ruxolitinib arm achieved hematocrit control, compared to 20% of those receiving standard therapy. And 38% of patients in the ruxolitinib arm had at least a 35% spleen reduction, compared to 1% of patients in the standard-therapy arm.

The rate of complete hematologic remission was significantly higher in the ruxolitinib group than in the standard-therapy group, at 24% and 9%, respectively (P=0.003).

And ruxolitinib-treated patients had a greater reduction in overall symptoms. Forty-nine percent of ruxolitinib-treated patients had at least a 50% reduction in their total symptom score at week 32 (as measured by the MPN-SAF 14-item total symptom score), compared to 5% of patients on standard therapy.

Based on these results, most patients in the standard-therapy arm crossed over to receive ruxolitinib immediately after week 32. So the researchers could only compare rates of adverse events through week 32.

They found that grade 3/4 anemia was more common with ruxolitinib than with standard therapy (2% and 0%, respectively). The same was true of grade 3/4 thrombocytopenia (5% and 4%, respectively) and herpes zoster infections of all grades (6% and 0%, respectively).

However, thromboembolic events were more common with standard therapy. They occurred in 6 patients who received standard therapy and 1 ruxolitinib-treated patient.

The most common non-hematologic adverse events in the ruxolitinib arm were headache (16%), diarrhea (15%), and fatigue (15%), which were mainly grade 1 or 2. The rates of these events in the standard therapy arm were 19%, 7%, and 15%, respectively.

The researchers also noted that nearly 85% of patients randomized to ruxolitinib were still receiving treatment at a median follow-up of 81 weeks.

Dimitrios Stamou, PhD

Credit: Jes Andersen/

University of Copenhagen

Researchers say they have discovered how Ras proteins find their proper place in cells, a finding that may aid the development of novel approaches to treat cancers.

The team noted that cancers develop if Ras proteins start to trigger misregulation, and Ras misregulates if it misses its correct location on the cell wall—the membrane.

What the researchers discovered is that Ras cannot reach its designated location if the membrane has the wrong shape.

“If the curvature of the cell is right, Ras goes to the right place,” said Dimitrios Stamou, PhD, of the University of Copenhagen in Denmark.

“If the membrane is too straight or too bent, it does not. And Ras is very much like any other worker. If it never finds the way to its workplace, it is not likely to get any work done.”

Dr Stamou and his colleagues described this discovery in Nature Chemical Biology.

Ras proteins are thought to be misregulated in upwards of 30% of all cancers. For 3 decades, researchers have been searching for ways to quell the killer protein.

Their lack of success has given Ras a reputation as the “undruggable cancer target,” but Dr Stamou believes we can change by moving in a new direction.

“If Ras goes off the rails because of changes in the curvature of the cell, perhaps we should target whatever changes the shape of the cell membrane,” he said.

Looking for a correlation between cell shape and Ras misregulation was unusual, even bordering on controversial, said study author Jannik Bruun Larsen, PhD, of the University of Copenhagen.

The researchers were investigating how Ras proteins attach themselves to the cell wall, and Dr Larsen tried to attach Ras to a variety of simulated cell membranes formed into small spheres or vesicles of varying sizes.

He found that Ras would attach more readily to smaller spheres, which were more curved than the large ones, and Dr Larsen started to see a pattern.

“For more than a decade, people thought that the constituents of the cell wall was the thing that controlled where Ras was localized,” Dr Larson said. “We have shown that at least one other aspect—namely, membrane curvature—governs where Ras ends up in the cell and is therefore likely to be a factor in cancer development.”

All of the research so far has been conducted in vitro. Dr Stamou said the next big challenge is to uncover how these effects play out in living systems.

“It will be 10 times more difficult to uncover these effects in living systems, but it needs to happen,” he said. “We have started, and we really hope others will follow. It may prove complicated to develop a drug that changes the shape of cells, but I am certain that the discovery of the shape/misregulation-correlation will at least lead to new ways to diagnose cancers.”

Dimitrios Stamou, PhD

Credit: Jes Andersen/

University of Copenhagen

Researchers say they have discovered how Ras proteins find their proper place in cells, a finding that may aid the development of novel approaches to treat cancers.

The team noted that cancers develop if Ras proteins start to trigger misregulation, and Ras misregulates if it misses its correct location on the cell wall—the membrane.

What the researchers discovered is that Ras cannot reach its designated location if the membrane has the wrong shape.

“If the curvature of the cell is right, Ras goes to the right place,” said Dimitrios Stamou, PhD, of the University of Copenhagen in Denmark.

“If the membrane is too straight or too bent, it does not. And Ras is very much like any other worker. If it never finds the way to its workplace, it is not likely to get any work done.”

Dr Stamou and his colleagues described this discovery in Nature Chemical Biology.

Ras proteins are thought to be misregulated in upwards of 30% of all cancers. For 3 decades, researchers have been searching for ways to quell the killer protein.

Their lack of success has given Ras a reputation as the “undruggable cancer target,” but Dr Stamou believes we can change by moving in a new direction.

“If Ras goes off the rails because of changes in the curvature of the cell, perhaps we should target whatever changes the shape of the cell membrane,” he said.

Looking for a correlation between cell shape and Ras misregulation was unusual, even bordering on controversial, said study author Jannik Bruun Larsen, PhD, of the University of Copenhagen.

The researchers were investigating how Ras proteins attach themselves to the cell wall, and Dr Larsen tried to attach Ras to a variety of simulated cell membranes formed into small spheres or vesicles of varying sizes.

He found that Ras would attach more readily to smaller spheres, which were more curved than the large ones, and Dr Larsen started to see a pattern.

“For more than a decade, people thought that the constituents of the cell wall was the thing that controlled where Ras was localized,” Dr Larson said. “We have shown that at least one other aspect—namely, membrane curvature—governs where Ras ends up in the cell and is therefore likely to be a factor in cancer development.”

All of the research so far has been conducted in vitro. Dr Stamou said the next big challenge is to uncover how these effects play out in living systems.

“It will be 10 times more difficult to uncover these effects in living systems, but it needs to happen,” he said. “We have started, and we really hope others will follow. It may prove complicated to develop a drug that changes the shape of cells, but I am certain that the discovery of the shape/misregulation-correlation will at least lead to new ways to diagnose cancers.”

Dimitrios Stamou, PhD

Credit: Jes Andersen/

University of Copenhagen

Researchers say they have discovered how Ras proteins find their proper place in cells, a finding that may aid the development of novel approaches to treat cancers.

The team noted that cancers develop if Ras proteins start to trigger misregulation, and Ras misregulates if it misses its correct location on the cell wall—the membrane.

What the researchers discovered is that Ras cannot reach its designated location if the membrane has the wrong shape.

“If the curvature of the cell is right, Ras goes to the right place,” said Dimitrios Stamou, PhD, of the University of Copenhagen in Denmark.

“If the membrane is too straight or too bent, it does not. And Ras is very much like any other worker. If it never finds the way to its workplace, it is not likely to get any work done.”

Dr Stamou and his colleagues described this discovery in Nature Chemical Biology.

Ras proteins are thought to be misregulated in upwards of 30% of all cancers. For 3 decades, researchers have been searching for ways to quell the killer protein.

Their lack of success has given Ras a reputation as the “undruggable cancer target,” but Dr Stamou believes we can change by moving in a new direction.

“If Ras goes off the rails because of changes in the curvature of the cell, perhaps we should target whatever changes the shape of the cell membrane,” he said.

Looking for a correlation between cell shape and Ras misregulation was unusual, even bordering on controversial, said study author Jannik Bruun Larsen, PhD, of the University of Copenhagen.

The researchers were investigating how Ras proteins attach themselves to the cell wall, and Dr Larsen tried to attach Ras to a variety of simulated cell membranes formed into small spheres or vesicles of varying sizes.

He found that Ras would attach more readily to smaller spheres, which were more curved than the large ones, and Dr Larsen started to see a pattern.

“For more than a decade, people thought that the constituents of the cell wall was the thing that controlled where Ras was localized,” Dr Larson said. “We have shown that at least one other aspect—namely, membrane curvature—governs where Ras ends up in the cell and is therefore likely to be a factor in cancer development.”

All of the research so far has been conducted in vitro. Dr Stamou said the next big challenge is to uncover how these effects play out in living systems.

“It will be 10 times more difficult to uncover these effects in living systems, but it needs to happen,” he said. “We have started, and we really hope others will follow. It may prove complicated to develop a drug that changes the shape of cells, but I am certain that the discovery of the shape/misregulation-correlation will at least lead to new ways to diagnose cancers.”

Researchers in the lab

Credit: Rhoda Baer

The detection and imaging of protein-protein interactions in live cells just got a lot more colorful, researchers have reported in Nature Methods.

The team created a  technique that converts biochemical processes into color changes that are easily visualized.

The group said this provides a new tool scientists can use to answer questions about fundamental mechanisms in cell biology, aid the discovery of novel therapeutics, and more.

Robert E. Campbell, PhD, of the University of Alberta in Edmonton, Alberta, Canada, and his colleagues conducted this research.

They developed the technique, dubbed FPX, that employs genetically encoded fluorescent proteins to image dynamic biochemical events in live cells and tissues. The FPX method converts a change in protein-protein interactions into a dramatic green to red (or vice versa) color change that is immediately visible.

“Strategies for converting fluorescent proteins into active biosensors of intracellular biochemistry are few in number and technically challenging,” Dr Campbell said. “With this development, we can immediately image activity happening at the cellular level, offering an alternative to existing methods for detecting and imaging of protein-protein interactions in live cells.”

The FPX method is based on green and red dimerization-dependent fluorescent proteins (ddFPs) that Dr Campbell and his colleagues first reported in 2012.

Yidan Ding, PhD, a research assistant at the University of Alberta and the primary contributor to this work, found she could combine the use of both green and red ddFPs in single cells, such that the proteins could be green or red, but not both, at the same time.

By introducing modified versions of the proteins into live cells, and taking advantage of the fact that green and red fluorescence are mutually exclusive, Dr Ding was able to construct a wide variety of biosensors that underwent dramatic changes in fluorescence in response to biochemical processes of interest.

By adding this new dimension to fluorescent proteins and engineering them to be biosensors that change their color in response to specific biological events, Drs Ding and Campbell and their colleagues have provided a tool for researchers to immediately pinpoint a major change at the cellular level.

This minimizes the need for extensive biosensor optimization and provides a versatile new approach to building the next generation of biosensors.

“This allows for a wide scope of applications,” Dr Campbell said. “It will be immediately relevant to many areas of fundamental cell biology research and practical applications such as drug discovery. Ultimately, it will help researchers achieve breakthroughs in a wide variety of areas in the life sciences, such as neuroscience, diabetes, and cancer.”

Dr Campbell has a patent pending on the technology.

Researchers in the lab

Credit: Rhoda Baer

The detection and imaging of protein-protein interactions in live cells just got a lot more colorful, researchers have reported in Nature Methods.

The team created a  technique that converts biochemical processes into color changes that are easily visualized.

The group said this provides a new tool scientists can use to answer questions about fundamental mechanisms in cell biology, aid the discovery of novel therapeutics, and more.

Robert E. Campbell, PhD, of the University of Alberta in Edmonton, Alberta, Canada, and his colleagues conducted this research.

They developed the technique, dubbed FPX, that employs genetically encoded fluorescent proteins to image dynamic biochemical events in live cells and tissues. The FPX method converts a change in protein-protein interactions into a dramatic green to red (or vice versa) color change that is immediately visible.

“Strategies for converting fluorescent proteins into active biosensors of intracellular biochemistry are few in number and technically challenging,” Dr Campbell said. “With this development, we can immediately image activity happening at the cellular level, offering an alternative to existing methods for detecting and imaging of protein-protein interactions in live cells.”

The FPX method is based on green and red dimerization-dependent fluorescent proteins (ddFPs) that Dr Campbell and his colleagues first reported in 2012.

Yidan Ding, PhD, a research assistant at the University of Alberta and the primary contributor to this work, found she could combine the use of both green and red ddFPs in single cells, such that the proteins could be green or red, but not both, at the same time.

By introducing modified versions of the proteins into live cells, and taking advantage of the fact that green and red fluorescence are mutually exclusive, Dr Ding was able to construct a wide variety of biosensors that underwent dramatic changes in fluorescence in response to biochemical processes of interest.

By adding this new dimension to fluorescent proteins and engineering them to be biosensors that change their color in response to specific biological events, Drs Ding and Campbell and their colleagues have provided a tool for researchers to immediately pinpoint a major change at the cellular level.

This minimizes the need for extensive biosensor optimization and provides a versatile new approach to building the next generation of biosensors.

“This allows for a wide scope of applications,” Dr Campbell said. “It will be immediately relevant to many areas of fundamental cell biology research and practical applications such as drug discovery. Ultimately, it will help researchers achieve breakthroughs in a wide variety of areas in the life sciences, such as neuroscience, diabetes, and cancer.”

Dr Campbell has a patent pending on the technology.

Researchers in the lab

Credit: Rhoda Baer

The detection and imaging of protein-protein interactions in live cells just got a lot more colorful, researchers have reported in Nature Methods.

The team created a  technique that converts biochemical processes into color changes that are easily visualized.

The group said this provides a new tool scientists can use to answer questions about fundamental mechanisms in cell biology, aid the discovery of novel therapeutics, and more.

Robert E. Campbell, PhD, of the University of Alberta in Edmonton, Alberta, Canada, and his colleagues conducted this research.

They developed the technique, dubbed FPX, that employs genetically encoded fluorescent proteins to image dynamic biochemical events in live cells and tissues. The FPX method converts a change in protein-protein interactions into a dramatic green to red (or vice versa) color change that is immediately visible.

“Strategies for converting fluorescent proteins into active biosensors of intracellular biochemistry are few in number and technically challenging,” Dr Campbell said. “With this development, we can immediately image activity happening at the cellular level, offering an alternative to existing methods for detecting and imaging of protein-protein interactions in live cells.”

The FPX method is based on green and red dimerization-dependent fluorescent proteins (ddFPs) that Dr Campbell and his colleagues first reported in 2012.

Yidan Ding, PhD, a research assistant at the University of Alberta and the primary contributor to this work, found she could combine the use of both green and red ddFPs in single cells, such that the proteins could be green or red, but not both, at the same time.

By introducing modified versions of the proteins into live cells, and taking advantage of the fact that green and red fluorescence are mutually exclusive, Dr Ding was able to construct a wide variety of biosensors that underwent dramatic changes in fluorescence in response to biochemical processes of interest.

By adding this new dimension to fluorescent proteins and engineering them to be biosensors that change their color in response to specific biological events, Drs Ding and Campbell and their colleagues have provided a tool for researchers to immediately pinpoint a major change at the cellular level.

This minimizes the need for extensive biosensor optimization and provides a versatile new approach to building the next generation of biosensors.

“This allows for a wide scope of applications,” Dr Campbell said. “It will be immediately relevant to many areas of fundamental cell biology research and practical applications such as drug discovery. Ultimately, it will help researchers achieve breakthroughs in a wide variety of areas in the life sciences, such as neuroscience, diabetes, and cancer.”

Dr Campbell has a patent pending on the technology.

Antihypertensive therapy would prevent about 56,000 cardiovascular events annually and 13,000 deaths from strokes, myocardial infarctions, and other causes if it were used by all U.S. adults who qualify for treatment under 2014 Joint National Committee hypertension guidelines, according to computer modeling published online Jan. 28 in the New England Journal of Medicine.

Even though the new Joint Committee guidelines are a bit less stringent than the committee’s prior 2003 advice, blood pressure remains inadequately controlled in 44% of the 64 million U.S. adults with hypertension, according to the investigators, led by Dr. Andrew Moran of Columbia University Medical Center, New York (N. Engl. J. Med. 2015;372:447-55).

The team used data from the National Health and Nutrition Examination Survey, the Framingham Heart Study, and other sources to estimate costs and benefits of expanding treatment to all U.S. adults aged 35-74 years who meet the 2014 benchmarks. They then calculated cost-effectiveness of expanding use in various subpopulations, using $50,000/quality-adjusted life-year (QALY) gained, or less, as their cut-off.

Overall, the investigators found that fuller implementation of the Joint Committee goals would pay for itself in reduced cardiovascular morbidity and mortality. The results were driven primarily by secondary prevention in patients with cardiovascular disease and primary prevention in patients with stage 2 hypertension, meaning systolic BP of 160 mm Hg or higher or diastolic BP of 100 mm Hg or higher.

“There is an enormous potential for improving population health by expanding treatment and improving control. Our findings clearly show that it would be worthwhile to significantly increase spending on office visits, home blood pressure monitoring, and interventions to improve treatment adherence. In fact, we could double treatment and monitoring spending for some patients – namely those with severe hypertension – and still break even,” Dr. Moran said in a statement announcing the results.

Treatment of patients with existing cardiovascular disease or stage 2 hypertension would save lives and costs in all men 35-74 years old and in women aged 45-74 years. The treatment of more modest hypertension – systolic BP of 140-159 mm Hg or a diastolic BP of 90-99 mm Hg – was cost effective for all men and for women also between the ages of 45 and 74 years, but treating women 35-44 years old with moderate hypertension and diabetes or kidney disease had intermediate cost-effectiveness ($125,000 per QALY), and low cost-effectiveness ($181,000 per QALY) if those comorbidities were not present.

“Some people will be alarmed about our conclusion that it may not be cost effective to treat hypertension in young adults, especially young women. It’s worth noting that our analysis didn’t capture the cumulative, lifetime effects of hypertension. It may well turn out to be cost effective to treat this group if we look at data on costs and benefits over several decades,” Dr. Moran said.

The team assumed a medication adherence rate of 75%. The costs of treatment included medications, monitoring, and drug side effects.

They did not analyze the effect of diet and lifestyle interventions for lowering blood pressure, or compare the cost-effectiveness of specific antihypertensive medication classes or combinations.

The work was funded by the National Heart, Lung, and Blood Institute, among others. The authors reported no relevant financial disclosures.

[email protected]

Antihypertensive therapy would prevent about 56,000 cardiovascular events annually and 13,000 deaths from strokes, myocardial infarctions, and other causes if it were used by all U.S. adults who qualify for treatment under 2014 Joint National Committee hypertension guidelines, according to computer modeling published online Jan. 28 in the New England Journal of Medicine.

Even though the new Joint Committee guidelines are a bit less stringent than the committee’s prior 2003 advice, blood pressure remains inadequately controlled in 44% of the 64 million U.S. adults with hypertension, according to the investigators, led by Dr. Andrew Moran of Columbia University Medical Center, New York (N. Engl. J. Med. 2015;372:447-55).

The team used data from the National Health and Nutrition Examination Survey, the Framingham Heart Study, and other sources to estimate costs and benefits of expanding treatment to all U.S. adults aged 35-74 years who meet the 2014 benchmarks. They then calculated cost-effectiveness of expanding use in various subpopulations, using $50,000/quality-adjusted life-year (QALY) gained, or less, as their cut-off.

Overall, the investigators found that fuller implementation of the Joint Committee goals would pay for itself in reduced cardiovascular morbidity and mortality. The results were driven primarily by secondary prevention in patients with cardiovascular disease and primary prevention in patients with stage 2 hypertension, meaning systolic BP of 160 mm Hg or higher or diastolic BP of 100 mm Hg or higher.

“There is an enormous potential for improving population health by expanding treatment and improving control. Our findings clearly show that it would be worthwhile to significantly increase spending on office visits, home blood pressure monitoring, and interventions to improve treatment adherence. In fact, we could double treatment and monitoring spending for some patients – namely those with severe hypertension – and still break even,” Dr. Moran said in a statement announcing the results.

Treatment of patients with existing cardiovascular disease or stage 2 hypertension would save lives and costs in all men 35-74 years old and in women aged 45-74 years. The treatment of more modest hypertension – systolic BP of 140-159 mm Hg or a diastolic BP of 90-99 mm Hg – was cost effective for all men and for women also between the ages of 45 and 74 years, but treating women 35-44 years old with moderate hypertension and diabetes or kidney disease had intermediate cost-effectiveness ($125,000 per QALY), and low cost-effectiveness ($181,000 per QALY) if those comorbidities were not present.

“Some people will be alarmed about our conclusion that it may not be cost effective to treat hypertension in young adults, especially young women. It’s worth noting that our analysis didn’t capture the cumulative, lifetime effects of hypertension. It may well turn out to be cost effective to treat this group if we look at data on costs and benefits over several decades,” Dr. Moran said.

The team assumed a medication adherence rate of 75%. The costs of treatment included medications, monitoring, and drug side effects.

They did not analyze the effect of diet and lifestyle interventions for lowering blood pressure, or compare the cost-effectiveness of specific antihypertensive medication classes or combinations.

The work was funded by the National Heart, Lung, and Blood Institute, among others. The authors reported no relevant financial disclosures.

[email protected]

Antihypertensive therapy would prevent about 56,000 cardiovascular events annually and 13,000 deaths from strokes, myocardial infarctions, and other causes if it were used by all U.S. adults who qualify for treatment under 2014 Joint National Committee hypertension guidelines, according to computer modeling published online Jan. 28 in the New England Journal of Medicine.

Even though the new Joint Committee guidelines are a bit less stringent than the committee’s prior 2003 advice, blood pressure remains inadequately controlled in 44% of the 64 million U.S. adults with hypertension, according to the investigators, led by Dr. Andrew Moran of Columbia University Medical Center, New York (N. Engl. J. Med. 2015;372:447-55).

The team used data from the National Health and Nutrition Examination Survey, the Framingham Heart Study, and other sources to estimate costs and benefits of expanding treatment to all U.S. adults aged 35-74 years who meet the 2014 benchmarks. They then calculated cost-effectiveness of expanding use in various subpopulations, using $50,000/quality-adjusted life-year (QALY) gained, or less, as their cut-off.

Overall, the investigators found that fuller implementation of the Joint Committee goals would pay for itself in reduced cardiovascular morbidity and mortality. The results were driven primarily by secondary prevention in patients with cardiovascular disease and primary prevention in patients with stage 2 hypertension, meaning systolic BP of 160 mm Hg or higher or diastolic BP of 100 mm Hg or higher.

“There is an enormous potential for improving population health by expanding treatment and improving control. Our findings clearly show that it would be worthwhile to significantly increase spending on office visits, home blood pressure monitoring, and interventions to improve treatment adherence. In fact, we could double treatment and monitoring spending for some patients – namely those with severe hypertension – and still break even,” Dr. Moran said in a statement announcing the results.

Treatment of patients with existing cardiovascular disease or stage 2 hypertension would save lives and costs in all men 35-74 years old and in women aged 45-74 years. The treatment of more modest hypertension – systolic BP of 140-159 mm Hg or a diastolic BP of 90-99 mm Hg – was cost effective for all men and for women also between the ages of 45 and 74 years, but treating women 35-44 years old with moderate hypertension and diabetes or kidney disease had intermediate cost-effectiveness ($125,000 per QALY), and low cost-effectiveness ($181,000 per QALY) if those comorbidities were not present.

“Some people will be alarmed about our conclusion that it may not be cost effective to treat hypertension in young adults, especially young women. It’s worth noting that our analysis didn’t capture the cumulative, lifetime effects of hypertension. It may well turn out to be cost effective to treat this group if we look at data on costs and benefits over several decades,” Dr. Moran said.

The team assumed a medication adherence rate of 75%. The costs of treatment included medications, monitoring, and drug side effects.

They did not analyze the effect of diet and lifestyle interventions for lowering blood pressure, or compare the cost-effectiveness of specific antihypertensive medication classes or combinations.

The work was funded by the National Heart, Lung, and Blood Institute, among others. The authors reported no relevant financial disclosures.

[email protected]