Emergency physicians (EPs) are trained to recognize and treat conditions that most severely affect patients at the extremes of age. For decades, the recognition and management of child neglect and abuse has been part of emergency medicine (EM) residency training and most states now require physicians to complete a child abuse course for licensing. In this issue, “Recognizing and Managing Elder Abuse in the Emergency Department” by Rosen et al describes abuse at the other age extreme. The thorough discussion following an illustrative case presentation raises serious concerns that the occurrence of elder neglect and abuse may be increasing in frequency in a rapidly aging population.

Child abuse and elder abuse share several common features along with some notable differences. When a member of either age group presents to the ED with fractures and/or soft tissue injuries, EPs must maintain a high index of suspicion for abuse, obtain a carefully directed history, and be able to recognize the characteristic patterns of injury. Hallmarks of both child abuse and elder abuse include a history provided by the caregiver that is not consistent with the actual injuries; an often-unobtainable independent history from an infant or baby not yet able to speak or an older adult with dementia; and a physical exam revealing bruises in areas that are not over bony prominences. A radiographic skeletal survey may show multiple fractures in various stages of healing, and laboratory testing may reveal nutritional evidence of neglect, medication over- or underdosing, or the presence of medications that have not been prescribed for the patient.

Patterns of abuse injuries in the two age groups differ. As noted by Colbourne and Clarke in Tintinalli’s Emergency Medicine (8^th ed, p. 1001), nonaccidental bruises in children are more common on the torso, neck, ears, cheeks, buttocks, and back; appear in clusters; are frequently symmetrical; and tend to be larger and more numerous than accidental injuries. Hand or implement patterns on the skin may be observed. Rib and metaphyseal fractures are unusual in children, as are all fractures at a very young age.

In the midst of an epidemic of elderly fall injuries, abuse injuries, as described in the pages ahead, most commonly occur on the head, neck, and upper extremities, and include large bruises on the face, lateral arm, or posterior torso. Based on preliminary results from an ongoing study, left periorbital, neck, and ulnar forearm injuries appear to be particularly indicative of abuse rather than accidental. An elderly person may be abused by an adult-child or relative living in the same household attempting to gain control over the victim’s wealth or residence.

Interventional resources required for both types of abuse, as well as for intimate partner abuse, are also similar and include safe facilities for extended treatment and separation from a suspected abuser; hospital security, legal, and administrative support; social services; law enforcement; psychiatric evaluation of adult capacity; and child or adult protective services, which, as Rosen et al note, operate very differently from one another. All states, except one, now require reporting of both child abuse and elder abuse.*

None of these comparisons of child abuse and elder abuse are meant to suggest equivalency—moral or otherwise. Children are not “little adults,” and the frail elderly are not truly “child-like.” Each incident of a child “slipping through the cracks” of the protective measures currently in place underscores the need for sufficient resources to deal with child abuse alone, and an increasing number of elder abuse cases should not compete with these needs. But implementing greater awareness, preventive measures, and physical and human resources to address these problems at both extremes of age cannot be put off for the future. 

When I started the first geriatric emergency medicine fellowship in the country in 2005, elder abuse was not even on my radar screen. Now it must be considered a serious and growing problem by all. 

*New York State alone does not require reporting of elder abuse.

Emergency physicians (EPs) are trained to recognize and treat conditions that most severely affect patients at the extremes of age. For decades, the recognition and management of child neglect and abuse has been part of emergency medicine (EM) residency training and most states now require physicians to complete a child abuse course for licensing. In this issue, “Recognizing and Managing Elder Abuse in the Emergency Department” by Rosen et al describes abuse at the other age extreme. The thorough discussion following an illustrative case presentation raises serious concerns that the occurrence of elder neglect and abuse may be increasing in frequency in a rapidly aging population.

Child abuse and elder abuse share several common features along with some notable differences. When a member of either age group presents to the ED with fractures and/or soft tissue injuries, EPs must maintain a high index of suspicion for abuse, obtain a carefully directed history, and be able to recognize the characteristic patterns of injury. Hallmarks of both child abuse and elder abuse include a history provided by the caregiver that is not consistent with the actual injuries; an often-unobtainable independent history from an infant or baby not yet able to speak or an older adult with dementia; and a physical exam revealing bruises in areas that are not over bony prominences. A radiographic skeletal survey may show multiple fractures in various stages of healing, and laboratory testing may reveal nutritional evidence of neglect, medication over- or underdosing, or the presence of medications that have not been prescribed for the patient.

Patterns of abuse injuries in the two age groups differ. As noted by Colbourne and Clarke in Tintinalli’s Emergency Medicine (8^th ed, p. 1001), nonaccidental bruises in children are more common on the torso, neck, ears, cheeks, buttocks, and back; appear in clusters; are frequently symmetrical; and tend to be larger and more numerous than accidental injuries. Hand or implement patterns on the skin may be observed. Rib and metaphyseal fractures are unusual in children, as are all fractures at a very young age.

In the midst of an epidemic of elderly fall injuries, abuse injuries, as described in the pages ahead, most commonly occur on the head, neck, and upper extremities, and include large bruises on the face, lateral arm, or posterior torso. Based on preliminary results from an ongoing study, left periorbital, neck, and ulnar forearm injuries appear to be particularly indicative of abuse rather than accidental. An elderly person may be abused by an adult-child or relative living in the same household attempting to gain control over the victim’s wealth or residence.

Interventional resources required for both types of abuse, as well as for intimate partner abuse, are also similar and include safe facilities for extended treatment and separation from a suspected abuser; hospital security, legal, and administrative support; social services; law enforcement; psychiatric evaluation of adult capacity; and child or adult protective services, which, as Rosen et al note, operate very differently from one another. All states, except one, now require reporting of both child abuse and elder abuse.*

None of these comparisons of child abuse and elder abuse are meant to suggest equivalency—moral or otherwise. Children are not “little adults,” and the frail elderly are not truly “child-like.” Each incident of a child “slipping through the cracks” of the protective measures currently in place underscores the need for sufficient resources to deal with child abuse alone, and an increasing number of elder abuse cases should not compete with these needs. But implementing greater awareness, preventive measures, and physical and human resources to address these problems at both extremes of age cannot be put off for the future. 

When I started the first geriatric emergency medicine fellowship in the country in 2005, elder abuse was not even on my radar screen. Now it must be considered a serious and growing problem by all. 

*New York State alone does not require reporting of elder abuse.

Emergency physicians (EPs) are trained to recognize and treat conditions that most severely affect patients at the extremes of age. For decades, the recognition and management of child neglect and abuse has been part of emergency medicine (EM) residency training and most states now require physicians to complete a child abuse course for licensing. In this issue, “Recognizing and Managing Elder Abuse in the Emergency Department” by Rosen et al describes abuse at the other age extreme. The thorough discussion following an illustrative case presentation raises serious concerns that the occurrence of elder neglect and abuse may be increasing in frequency in a rapidly aging population.

Child abuse and elder abuse share several common features along with some notable differences. When a member of either age group presents to the ED with fractures and/or soft tissue injuries, EPs must maintain a high index of suspicion for abuse, obtain a carefully directed history, and be able to recognize the characteristic patterns of injury. Hallmarks of both child abuse and elder abuse include a history provided by the caregiver that is not consistent with the actual injuries; an often-unobtainable independent history from an infant or baby not yet able to speak or an older adult with dementia; and a physical exam revealing bruises in areas that are not over bony prominences. A radiographic skeletal survey may show multiple fractures in various stages of healing, and laboratory testing may reveal nutritional evidence of neglect, medication over- or underdosing, or the presence of medications that have not been prescribed for the patient.

Patterns of abuse injuries in the two age groups differ. As noted by Colbourne and Clarke in Tintinalli’s Emergency Medicine (8^th ed, p. 1001), nonaccidental bruises in children are more common on the torso, neck, ears, cheeks, buttocks, and back; appear in clusters; are frequently symmetrical; and tend to be larger and more numerous than accidental injuries. Hand or implement patterns on the skin may be observed. Rib and metaphyseal fractures are unusual in children, as are all fractures at a very young age.

In the midst of an epidemic of elderly fall injuries, abuse injuries, as described in the pages ahead, most commonly occur on the head, neck, and upper extremities, and include large bruises on the face, lateral arm, or posterior torso. Based on preliminary results from an ongoing study, left periorbital, neck, and ulnar forearm injuries appear to be particularly indicative of abuse rather than accidental. An elderly person may be abused by an adult-child or relative living in the same household attempting to gain control over the victim’s wealth or residence.

Interventional resources required for both types of abuse, as well as for intimate partner abuse, are also similar and include safe facilities for extended treatment and separation from a suspected abuser; hospital security, legal, and administrative support; social services; law enforcement; psychiatric evaluation of adult capacity; and child or adult protective services, which, as Rosen et al note, operate very differently from one another. All states, except one, now require reporting of both child abuse and elder abuse.*

None of these comparisons of child abuse and elder abuse are meant to suggest equivalency—moral or otherwise. Children are not “little adults,” and the frail elderly are not truly “child-like.” Each incident of a child “slipping through the cracks” of the protective measures currently in place underscores the need for sufficient resources to deal with child abuse alone, and an increasing number of elder abuse cases should not compete with these needs. But implementing greater awareness, preventive measures, and physical and human resources to address these problems at both extremes of age cannot be put off for the future. 

When I started the first geriatric emergency medicine fellowship in the country in 2005, elder abuse was not even on my radar screen. Now it must be considered a serious and growing problem by all. 

*New York State alone does not require reporting of elder abuse.

Editor’s Note: This article has been adapted from an article originally published in Federal Practitioner (Tavakoli HR, et al. Kratom: a new product in an expanding substance abuse market. Fed Prac. 2016;33[11]:132-136. http://www.fedprac.com).

According to the United Nations Office on Drugs and Crime, the last decade saw an alarming rise in the use of recreational substances.¹ There was an escalation not only in the use of the more well-known street drugs (cannabis, stimulants, opioids, and hallucinogens), but also an exponential increase in the abuse of novel psychoactive substances. Although most emergency physicians (EPs) are at least relatively familiar with some of these designer drugs—often synthesized analogues of common street drugs—region-specific herbal products with psychoactive properties are now entering the market worldwide. Certainly, the cause of this increased use is multifactorial: Ease of access to these drugs and ambiguous legality are believed to be among the largest contributors. Infrastructure established through globalization promotes easy drug transportation and distribution across borders, and widespread Internet use makes knowledge of and accessibility to such substances exceedingly simple.^2,3

In particular, widespread online access has permanently altered the acquisition of knowledge in all realms—including drug use. Although Erowid Center remains one of the oldest and best-known of this type of Web site and bills itself as providing “harm reduction,” others have cropped up online and disseminate information about many forms of potentially psychoactive substances. Despite the purported raison d’être of these Web sites, recent studies have demonstrated these sites’ efficacy in promoting drug use under the guise of safety, particularly among adolescents and young adults. Among these is a qualitative study by Boyer et al⁴ of 12 drug users admitted to a pediatric psychiatry unit. Through extensive questioning about the patients’ digital habits, the researchers demonstrated that the majority of subjects used these Web sites and, as a result, either increased their drug use or learned about (and tried) new substances.

One drug that has benefited from globalization and the Internet is kratom (Mitragyna speciosa korth). This formerly regionally confined herbal psychoactive substance is native to Southeast Asia, where it has been used (and abused) for centuries as a mild stimulant, to prevent opioid withdrawal, and for recreational purposes. In recent years, kratom has been marketed as a psychotropic drug and has become increasingly popular in the United States and in the United Kingdom.^2,5,6 In the United States, this poses a problem for EPs who often are unaware of this plant’s existence, much less its abuse potential or health effects.² Also known as ketum, kakuam, thang, thom, or biak, kratom is marketed in stores and online as a cheap, safe alternative to opioids.

Although considered a “substance of concern” without any approved medical use by the US Drug Enforcement Agency (DEA), kratom is not a regulated or controlled substance in the United States.³ In late 2016, out of concern for public safety, the DEA placed a temporary ban on kratom. The Agency’s move was followed by a substantial negative reaction from kratom supporters and was quickly rescinded. As of April 2017, the DEA did not have a timetable for banning or scheduling the drug, though some states have banned it.

To that end, users consider kratom a legal high, and it is easily purchased online. A 2010 study in the United Kingdom examined Web sites where kratom and many other quasilegal substances (including Salvia divinorum and legal precursors to LSD) could be purchased for an average of £10 (about $13 US currency).⁵ This study’s authors also noted a significant lack of product information on these marketplaces. As these products are not overseen by any regulatory body, the risk of overdose or adulteration is extremely high.^2,3,6-8 In fact, Krypton, a kratom product sold online, was found to be adulterated with O-desmethyltramadol—the active metabolite of the synthetic opiate tramadol—and implicated in at least nine deaths.⁷

This article presents a case of kratom abuse. It describes a brief history of the substance, its pharmacological characteristics, the clinical presentation of kratom abuse, and the treatment of kratom-related illness and evaluation of potential toxic sequelae. In light of the rapid proliferation of kratom in the United States, a basic working knowledge of the drug is quickly becoming a must for EPs.

Case Presentation

At his employer’s request, a 33-year-old man presented to his family physician for a worsening of his uncontrolled back pain from a herniated lumbar disk resulting from a motor vehicle collision 3 months before. At his physician’s office he stated, “I don’t care if I live or die, I’m tired of the pain,” and “I’m going to go off on somebody if I can’t get this pain under control.” He also endorsed having auditory hallucinations for several years and a history of violence and homicide. The problem arose precipitously after he became concerned that he was abusing his opioid medication, and it was discontinued. The patient was transferred to the local ED and admitted to the psychiatric service for his suicidal ideations and risk of harming self and others.

On admission to the psychiatric service, the patient complained of body aches, chills, rhinorrhea, and significantly worsened irritability from his baseline, consistent with opioid withdrawal. Initial point-of-care (POC) admission drug testing had been negative as had expanded urine tests looking for synthetic opioids, cannabinoids, and cathinones. The patient reported no opioid use but was unable to explain his current symptom patterns, which were worsening his chronic pain and hampering any attempt to build rapport. On hospital day 3, the patient’s opioid withdrawal resolved, and psychiatric treatment was able to progress fully. On hospital day 4, the inpatient treatment team received a message from the patient’s primary care manager stating that a friend of the patient had found a bottle of herbal pills in the patient’s car. This was later revealed to be a kratom formulation that he had purchased online.

Background

Kratom is the colloquial name of a tree that is native to Thailand, Malaysia, and other countries in Southeast Asia. These trees, which can grow to 50 feet high and 15 feet wide, have long been the source of herbal remedies in Southeast Asia.^2,3 The leaves of these trees contain psychoactive substances that have a variety of effects when consumed. At low doses, kratom causes a stimulant effect (akin to the leaves of the coca plant in South America); laborers and farmers often use it to help boost their energy. At higher doses, kratom causes an opioid-like effect, which at mega doses produces an intense euphoric state and has led to a steady growth in abuse worldwide. Although the government of Thailand banned the planting of Mitragyna speciosa as early as 1943, its continued proliferation in Southeast Asia and throughout the world has not ceased.^2,3,6

In the United Kingdom, kratom is currently the second most common drug that is considered a legal high, only behind salvia (Salvia divinorum), a hallucinogenic herb that is better known as a result of its use by young celebrities over the past decade.^5,8

Kratom can be taken in a variety of ways: Crushed leaves often are placed in gel caps and swallowed; it can be drunk as a tea, juice, or boiled syrup; and it can be smoked or insufflated.^2,3,5,6

Pharmacology and Clinical Presentation

More than 20 psychoactive compounds have been isolated from kratom. Although a discussion of all these compounds is beyond the scope of this review, the two major compounds are mitragynine and 7-hydroxymitragynine.

Mitragynine

Mitragynine, the most abundant psychoactive compound found in kratom, is an indole alkaloid (Figure 1). Extraction and analysis of this compound has demonstrated numerous effects on multiple receptors, including mu-, delta-, and kappa-opioid receptors, leading to its opioid-like effects, including analgesia and euphoria. Also similar to common opioids, withdrawal symptomatology can present after only 5 days of daily use. There is limited evidence that mitragynine can activate postsynaptic alpha-2 adrenergic receptors, which may act synergistically with the mu-agonist with regard to its analgesic effect.^2,5

7-Hydroxymitragynine

7-hydroxymitragynine, despite being far less concentrated in kratom preparations, is about 13 times more potent than morphine and 46 times more potent than mitragynine. It is thought that its hydroxyl side chain added to C7 (Figure 2) adds to its lipophilicity and ability to cross the blood-brain barrier at a far more rapid rate than that of mitragynine.²

Mitragynine and 7-hydroxymitragynine remain the best-studied psychoactive components of kratom at this time. Other compounds that have been isolated, such as speciociliatine, paynantheine, and speciogynine, may play a role in kratom’s analgesic and psychoactive effects. Animal studies have demonstrated antimuscarinic properties in these compounds, but the properties do not seem to have any demonstrable effect at the opioid receptors.²

Intoxication and Withdrawal

Due to its increasing worldwide popularity, it is now imperative for EPs to be aware of the presentation of patients with kratom abuse as well as the management of withdrawal in light of its dependence potential. However, large-scale studies have not been performed, and much of the evidence comes not from the medical literature but from Web sites such as Erowid or SageWisdom.^2,5-9 To that end, such information will be discussed along with the limited research and expert consensuses available in peer-reviewed medical literature.

Kratom seems to have dose-dependent effects. At low doses (1-5 g of raw crushed leaves), kratom abusers often report a mild energizing effect, thought to be secondary to the stimulant properties of kratom’s multiple alkaloids. Users have reported mild euphoria and highs similar to those of the abuse of methylphenidate or modafinil.^2,9,10 Also similar to abuse of those substances, users have reported anxiety, irritability, and aggressiveness as a result of the stimulant-like effects.

At moderate-to-high doses (5-15 g of raw crushed leaves), it is believed that the mu-opiate receptor agonism overtakes the stimulant effects, leading to the euphoria, relaxation, and analgesia seen with conventional opioid use and abuse.^2,10 In light of the drug’s substantial binding and agonism of all opioid receptors, constipation and itching also are seen.² As such, if an individual is intoxicated, he or she should be managed with supportive and symptomatic care and continuous monitoring of heart rate, blood pressure, respiratory rate, and oxygen saturation.^2,10 Kratom intoxication can precipitate psychotic episodes similar to those caused by opiate intoxication, so monitoring for agitation or psychotic behaviors is also indicated.^9,10

The medical management of a patient with an acute kratom overdose (typically requiring ingestion of >15 g of crushed leaves) begins with addressing airway support, breathing, and circulation along with continuous vital sign monitoring and laboratory testing, including POC glucose testing, complete blood count, electrolytes, lactate, venous blood gas, and measurable drug levels (ethanol, acetaminophen, tricyclic antidepressants, as indicated).¹¹ If it is determined that kratom was the intoxicant, the greatest concern of death is similar to that of opioid overdose: respiratory depression. Although there are no large-scale human studies demonstrating efficacy, multiple authors suggest the use of naloxone in kratom-related hypoventilation.^9,10

The development of dependence on kratom and its subsequent withdrawal phenomena are thought to be similar to that of opioids, in light of its strong mu agonism.^2,5,9,10 Indeed, kratom has a long history of being used by opioid-dependent patients as an attempt to quit drug abuse or stave off debilitating withdrawal symptoms when they are unable to acquire their substance of choice.^2,5-10 As such, withdrawal and the treatment thereof will also mimic that of opioid withdrawal.

The kratom-dependent individual will often present with rhinorrhea, lacrimation, dry mouth, hostility, aggression, and emotional lability similar to the case study described earlier.^2,9,10 Kratom withdrawal, much like intoxication, also may precipitate or worsen psychotic symptoms, and monitoring is necessary throughout the detoxification process.^2,5,10 Withdrawal management should proceed along ambulatory clinic or hospital opioid withdrawal protocols that include step-down administration of opioids or with nonopioid medications for symptomatic relief, including muscle relaxants, alpha-2 agonists, and antidiarrheal agents.^5,9,10

Kratom Toxicity

A review of the available medical literature has demonstrated a number of toxic effects with kratom abuse, either as the sole agent or in concert with prescribed medications, recreational coingestants, or as a result of manufacturer’s adulteration with other chemicals or drugs. Of particular interest to EPs are manic or psychotic episode precipitation, seizure, hypothyroidism, intrahepatic cholestatic injury, and even sudden cardiac death.^2,3,5-10 In addition to the basic history, physical, and laboratory examination, the workup of patients identified as kratom users should include the following:

• Fastidious medication reconciliation with drug-interaction check;
• Exhaustive substance abuse history;
• Identification of the brand name and source of kratom purchased, to determine whether there are advertised coingestants or reports of adulteration;
• Electrocardiogram;
• Thyroid function testing;
• Hepatic function testing; and
• Comprehensive neurological and mental status examinations.

In chronic users of kratom, a number of effects have been seen whose etiologies have not yet been determined. These effects include depression, anxiety, tremulousness, weight loss, and psychosis.^3-7 Additionally, a study by Kittirattanapaiboon et al¹² correlated drug use by those with concurrent mental health disorders (in particular, kratom, which was used in 59% of the ≥14,000 individuals included in the study sample) with statistically significant higher suicide risk.

Detection

Because kratom is a relatively new compound in the United States, medical and forensic laboratories are only now implementing kratom detection protocols. Many laboratories now use high-performance liquid chromatography to analyze for mitragynine, 7-hydroxymitragynine, and two metabolites of mitragynine in urine.⁷ Le et al¹³ were able to detect mitragynine in the urine in levels as low as 1 ng/mL, which is clinically useful as mitragynine has a half-life determined in animal studies to be 3.85 hours. Similar detection limits for mitragynine and 7-hydroxymitragynine are used only at the Naval Medical Center Portsmouth in Virginia; however, kratom was not detected in the case study patient’s urine because a urine test was not done until hospital day 5.

Case Conclusion

When gently confronted about the kratom found in his car, the case study patient admitted that he had purchased kratom online after he was “cut off” from prescription opioids for his pain. He admitted that although it was beneficial for his pain, he did notice worsening in his aggression toward his spouse and coworkers. This progressed to an exacerbation of his psychotic symptoms of hallucinations and persecutory delusions. These symptoms remained well hidden—but were present for years prior to his presentation at the hospital. The patient was discharged from the inpatient psychiatric unit on hospital day 16 with a diagnosis of schizoaffective disorder, depressive type in addition to opioid-use disorder. The patient agreed to seek a pain management specialist and discontinue kratom use.

Conclusion

Kratom is an emerging drug of abuse in the Western world. Although significant research is being conducted on its possible medical uses, little is known about kratom beyond the “trip reports” of kratom users posted online. Because of its technically legal status in the United States and multiple other Western countries, kratom is easily accessible. Emergency physicians need to be aware of kratom, and during their evaluations, question appropriate patients about kratom and other legal highs.

Editor’s Note: This article has been adapted from an article originally published in Federal Practitioner (Tavakoli HR, et al. Kratom: a new product in an expanding substance abuse market. Fed Prac. 2016;33[11]:132-136. http://www.fedprac.com).

According to the United Nations Office on Drugs and Crime, the last decade saw an alarming rise in the use of recreational substances.¹ There was an escalation not only in the use of the more well-known street drugs (cannabis, stimulants, opioids, and hallucinogens), but also an exponential increase in the abuse of novel psychoactive substances. Although most emergency physicians (EPs) are at least relatively familiar with some of these designer drugs—often synthesized analogues of common street drugs—region-specific herbal products with psychoactive properties are now entering the market worldwide. Certainly, the cause of this increased use is multifactorial: Ease of access to these drugs and ambiguous legality are believed to be among the largest contributors. Infrastructure established through globalization promotes easy drug transportation and distribution across borders, and widespread Internet use makes knowledge of and accessibility to such substances exceedingly simple.^2,3

In particular, widespread online access has permanently altered the acquisition of knowledge in all realms—including drug use. Although Erowid Center remains one of the oldest and best-known of this type of Web site and bills itself as providing “harm reduction,” others have cropped up online and disseminate information about many forms of potentially psychoactive substances. Despite the purported raison d’être of these Web sites, recent studies have demonstrated these sites’ efficacy in promoting drug use under the guise of safety, particularly among adolescents and young adults. Among these is a qualitative study by Boyer et al⁴ of 12 drug users admitted to a pediatric psychiatry unit. Through extensive questioning about the patients’ digital habits, the researchers demonstrated that the majority of subjects used these Web sites and, as a result, either increased their drug use or learned about (and tried) new substances.

One drug that has benefited from globalization and the Internet is kratom (Mitragyna speciosa korth). This formerly regionally confined herbal psychoactive substance is native to Southeast Asia, where it has been used (and abused) for centuries as a mild stimulant, to prevent opioid withdrawal, and for recreational purposes. In recent years, kratom has been marketed as a psychotropic drug and has become increasingly popular in the United States and in the United Kingdom.^2,5,6 In the United States, this poses a problem for EPs who often are unaware of this plant’s existence, much less its abuse potential or health effects.² Also known as ketum, kakuam, thang, thom, or biak, kratom is marketed in stores and online as a cheap, safe alternative to opioids.

Although considered a “substance of concern” without any approved medical use by the US Drug Enforcement Agency (DEA), kratom is not a regulated or controlled substance in the United States.³ In late 2016, out of concern for public safety, the DEA placed a temporary ban on kratom. The Agency’s move was followed by a substantial negative reaction from kratom supporters and was quickly rescinded. As of April 2017, the DEA did not have a timetable for banning or scheduling the drug, though some states have banned it.

To that end, users consider kratom a legal high, and it is easily purchased online. A 2010 study in the United Kingdom examined Web sites where kratom and many other quasilegal substances (including Salvia divinorum and legal precursors to LSD) could be purchased for an average of £10 (about $13 US currency).⁵ This study’s authors also noted a significant lack of product information on these marketplaces. As these products are not overseen by any regulatory body, the risk of overdose or adulteration is extremely high.^2,3,6-8 In fact, Krypton, a kratom product sold online, was found to be adulterated with O-desmethyltramadol—the active metabolite of the synthetic opiate tramadol—and implicated in at least nine deaths.⁷

This article presents a case of kratom abuse. It describes a brief history of the substance, its pharmacological characteristics, the clinical presentation of kratom abuse, and the treatment of kratom-related illness and evaluation of potential toxic sequelae. In light of the rapid proliferation of kratom in the United States, a basic working knowledge of the drug is quickly becoming a must for EPs.

Case Presentation

At his employer’s request, a 33-year-old man presented to his family physician for a worsening of his uncontrolled back pain from a herniated lumbar disk resulting from a motor vehicle collision 3 months before. At his physician’s office he stated, “I don’t care if I live or die, I’m tired of the pain,” and “I’m going to go off on somebody if I can’t get this pain under control.” He also endorsed having auditory hallucinations for several years and a history of violence and homicide. The problem arose precipitously after he became concerned that he was abusing his opioid medication, and it was discontinued. The patient was transferred to the local ED and admitted to the psychiatric service for his suicidal ideations and risk of harming self and others.

On admission to the psychiatric service, the patient complained of body aches, chills, rhinorrhea, and significantly worsened irritability from his baseline, consistent with opioid withdrawal. Initial point-of-care (POC) admission drug testing had been negative as had expanded urine tests looking for synthetic opioids, cannabinoids, and cathinones. The patient reported no opioid use but was unable to explain his current symptom patterns, which were worsening his chronic pain and hampering any attempt to build rapport. On hospital day 3, the patient’s opioid withdrawal resolved, and psychiatric treatment was able to progress fully. On hospital day 4, the inpatient treatment team received a message from the patient’s primary care manager stating that a friend of the patient had found a bottle of herbal pills in the patient’s car. This was later revealed to be a kratom formulation that he had purchased online.

Background

Kratom is the colloquial name of a tree that is native to Thailand, Malaysia, and other countries in Southeast Asia. These trees, which can grow to 50 feet high and 15 feet wide, have long been the source of herbal remedies in Southeast Asia.^2,3 The leaves of these trees contain psychoactive substances that have a variety of effects when consumed. At low doses, kratom causes a stimulant effect (akin to the leaves of the coca plant in South America); laborers and farmers often use it to help boost their energy. At higher doses, kratom causes an opioid-like effect, which at mega doses produces an intense euphoric state and has led to a steady growth in abuse worldwide. Although the government of Thailand banned the planting of Mitragyna speciosa as early as 1943, its continued proliferation in Southeast Asia and throughout the world has not ceased.^2,3,6

In the United Kingdom, kratom is currently the second most common drug that is considered a legal high, only behind salvia (Salvia divinorum), a hallucinogenic herb that is better known as a result of its use by young celebrities over the past decade.^5,8

Kratom can be taken in a variety of ways: Crushed leaves often are placed in gel caps and swallowed; it can be drunk as a tea, juice, or boiled syrup; and it can be smoked or insufflated.^2,3,5,6

Pharmacology and Clinical Presentation

More than 20 psychoactive compounds have been isolated from kratom. Although a discussion of all these compounds is beyond the scope of this review, the two major compounds are mitragynine and 7-hydroxymitragynine.

Mitragynine

Mitragynine, the most abundant psychoactive compound found in kratom, is an indole alkaloid (Figure 1). Extraction and analysis of this compound has demonstrated numerous effects on multiple receptors, including mu-, delta-, and kappa-opioid receptors, leading to its opioid-like effects, including analgesia and euphoria. Also similar to common opioids, withdrawal symptomatology can present after only 5 days of daily use. There is limited evidence that mitragynine can activate postsynaptic alpha-2 adrenergic receptors, which may act synergistically with the mu-agonist with regard to its analgesic effect.^2,5

7-Hydroxymitragynine

7-hydroxymitragynine, despite being far less concentrated in kratom preparations, is about 13 times more potent than morphine and 46 times more potent than mitragynine. It is thought that its hydroxyl side chain added to C7 (Figure 2) adds to its lipophilicity and ability to cross the blood-brain barrier at a far more rapid rate than that of mitragynine.²

Mitragynine and 7-hydroxymitragynine remain the best-studied psychoactive components of kratom at this time. Other compounds that have been isolated, such as speciociliatine, paynantheine, and speciogynine, may play a role in kratom’s analgesic and psychoactive effects. Animal studies have demonstrated antimuscarinic properties in these compounds, but the properties do not seem to have any demonstrable effect at the opioid receptors.²

Intoxication and Withdrawal

Due to its increasing worldwide popularity, it is now imperative for EPs to be aware of the presentation of patients with kratom abuse as well as the management of withdrawal in light of its dependence potential. However, large-scale studies have not been performed, and much of the evidence comes not from the medical literature but from Web sites such as Erowid or SageWisdom.^2,5-9 To that end, such information will be discussed along with the limited research and expert consensuses available in peer-reviewed medical literature.

Kratom seems to have dose-dependent effects. At low doses (1-5 g of raw crushed leaves), kratom abusers often report a mild energizing effect, thought to be secondary to the stimulant properties of kratom’s multiple alkaloids. Users have reported mild euphoria and highs similar to those of the abuse of methylphenidate or modafinil.^2,9,10 Also similar to abuse of those substances, users have reported anxiety, irritability, and aggressiveness as a result of the stimulant-like effects.

At moderate-to-high doses (5-15 g of raw crushed leaves), it is believed that the mu-opiate receptor agonism overtakes the stimulant effects, leading to the euphoria, relaxation, and analgesia seen with conventional opioid use and abuse.^2,10 In light of the drug’s substantial binding and agonism of all opioid receptors, constipation and itching also are seen.² As such, if an individual is intoxicated, he or she should be managed with supportive and symptomatic care and continuous monitoring of heart rate, blood pressure, respiratory rate, and oxygen saturation.^2,10 Kratom intoxication can precipitate psychotic episodes similar to those caused by opiate intoxication, so monitoring for agitation or psychotic behaviors is also indicated.^9,10

The medical management of a patient with an acute kratom overdose (typically requiring ingestion of >15 g of crushed leaves) begins with addressing airway support, breathing, and circulation along with continuous vital sign monitoring and laboratory testing, including POC glucose testing, complete blood count, electrolytes, lactate, venous blood gas, and measurable drug levels (ethanol, acetaminophen, tricyclic antidepressants, as indicated).¹¹ If it is determined that kratom was the intoxicant, the greatest concern of death is similar to that of opioid overdose: respiratory depression. Although there are no large-scale human studies demonstrating efficacy, multiple authors suggest the use of naloxone in kratom-related hypoventilation.^9,10

The development of dependence on kratom and its subsequent withdrawal phenomena are thought to be similar to that of opioids, in light of its strong mu agonism.^2,5,9,10 Indeed, kratom has a long history of being used by opioid-dependent patients as an attempt to quit drug abuse or stave off debilitating withdrawal symptoms when they are unable to acquire their substance of choice.^2,5-10 As such, withdrawal and the treatment thereof will also mimic that of opioid withdrawal.

The kratom-dependent individual will often present with rhinorrhea, lacrimation, dry mouth, hostility, aggression, and emotional lability similar to the case study described earlier.^2,9,10 Kratom withdrawal, much like intoxication, also may precipitate or worsen psychotic symptoms, and monitoring is necessary throughout the detoxification process.^2,5,10 Withdrawal management should proceed along ambulatory clinic or hospital opioid withdrawal protocols that include step-down administration of opioids or with nonopioid medications for symptomatic relief, including muscle relaxants, alpha-2 agonists, and antidiarrheal agents.^5,9,10

Kratom Toxicity

A review of the available medical literature has demonstrated a number of toxic effects with kratom abuse, either as the sole agent or in concert with prescribed medications, recreational coingestants, or as a result of manufacturer’s adulteration with other chemicals or drugs. Of particular interest to EPs are manic or psychotic episode precipitation, seizure, hypothyroidism, intrahepatic cholestatic injury, and even sudden cardiac death.^2,3,5-10 In addition to the basic history, physical, and laboratory examination, the workup of patients identified as kratom users should include the following:

• Fastidious medication reconciliation with drug-interaction check;
• Exhaustive substance abuse history;
• Identification of the brand name and source of kratom purchased, to determine whether there are advertised coingestants or reports of adulteration;
• Electrocardiogram;
• Thyroid function testing;
• Hepatic function testing; and
• Comprehensive neurological and mental status examinations.

In chronic users of kratom, a number of effects have been seen whose etiologies have not yet been determined. These effects include depression, anxiety, tremulousness, weight loss, and psychosis.^3-7 Additionally, a study by Kittirattanapaiboon et al¹² correlated drug use by those with concurrent mental health disorders (in particular, kratom, which was used in 59% of the ≥14,000 individuals included in the study sample) with statistically significant higher suicide risk.

Detection

Because kratom is a relatively new compound in the United States, medical and forensic laboratories are only now implementing kratom detection protocols. Many laboratories now use high-performance liquid chromatography to analyze for mitragynine, 7-hydroxymitragynine, and two metabolites of mitragynine in urine.⁷ Le et al¹³ were able to detect mitragynine in the urine in levels as low as 1 ng/mL, which is clinically useful as mitragynine has a half-life determined in animal studies to be 3.85 hours. Similar detection limits for mitragynine and 7-hydroxymitragynine are used only at the Naval Medical Center Portsmouth in Virginia; however, kratom was not detected in the case study patient’s urine because a urine test was not done until hospital day 5.

Case Conclusion

When gently confronted about the kratom found in his car, the case study patient admitted that he had purchased kratom online after he was “cut off” from prescription opioids for his pain. He admitted that although it was beneficial for his pain, he did notice worsening in his aggression toward his spouse and coworkers. This progressed to an exacerbation of his psychotic symptoms of hallucinations and persecutory delusions. These symptoms remained well hidden—but were present for years prior to his presentation at the hospital. The patient was discharged from the inpatient psychiatric unit on hospital day 16 with a diagnosis of schizoaffective disorder, depressive type in addition to opioid-use disorder. The patient agreed to seek a pain management specialist and discontinue kratom use.

Conclusion

Kratom is an emerging drug of abuse in the Western world. Although significant research is being conducted on its possible medical uses, little is known about kratom beyond the “trip reports” of kratom users posted online. Because of its technically legal status in the United States and multiple other Western countries, kratom is easily accessible. Emergency physicians need to be aware of kratom, and during their evaluations, question appropriate patients about kratom and other legal highs.

Editor’s Note: This article has been adapted from an article originally published in Federal Practitioner (Tavakoli HR, et al. Kratom: a new product in an expanding substance abuse market. Fed Prac. 2016;33[11]:132-136. http://www.fedprac.com).

According to the United Nations Office on Drugs and Crime, the last decade saw an alarming rise in the use of recreational substances.¹ There was an escalation not only in the use of the more well-known street drugs (cannabis, stimulants, opioids, and hallucinogens), but also an exponential increase in the abuse of novel psychoactive substances. Although most emergency physicians (EPs) are at least relatively familiar with some of these designer drugs—often synthesized analogues of common street drugs—region-specific herbal products with psychoactive properties are now entering the market worldwide. Certainly, the cause of this increased use is multifactorial: Ease of access to these drugs and ambiguous legality are believed to be among the largest contributors. Infrastructure established through globalization promotes easy drug transportation and distribution across borders, and widespread Internet use makes knowledge of and accessibility to such substances exceedingly simple.^2,3

In particular, widespread online access has permanently altered the acquisition of knowledge in all realms—including drug use. Although Erowid Center remains one of the oldest and best-known of this type of Web site and bills itself as providing “harm reduction,” others have cropped up online and disseminate information about many forms of potentially psychoactive substances. Despite the purported raison d’être of these Web sites, recent studies have demonstrated these sites’ efficacy in promoting drug use under the guise of safety, particularly among adolescents and young adults. Among these is a qualitative study by Boyer et al⁴ of 12 drug users admitted to a pediatric psychiatry unit. Through extensive questioning about the patients’ digital habits, the researchers demonstrated that the majority of subjects used these Web sites and, as a result, either increased their drug use or learned about (and tried) new substances.

One drug that has benefited from globalization and the Internet is kratom (Mitragyna speciosa korth). This formerly regionally confined herbal psychoactive substance is native to Southeast Asia, where it has been used (and abused) for centuries as a mild stimulant, to prevent opioid withdrawal, and for recreational purposes. In recent years, kratom has been marketed as a psychotropic drug and has become increasingly popular in the United States and in the United Kingdom.^2,5,6 In the United States, this poses a problem for EPs who often are unaware of this plant’s existence, much less its abuse potential or health effects.² Also known as ketum, kakuam, thang, thom, or biak, kratom is marketed in stores and online as a cheap, safe alternative to opioids.

Although considered a “substance of concern” without any approved medical use by the US Drug Enforcement Agency (DEA), kratom is not a regulated or controlled substance in the United States.³ In late 2016, out of concern for public safety, the DEA placed a temporary ban on kratom. The Agency’s move was followed by a substantial negative reaction from kratom supporters and was quickly rescinded. As of April 2017, the DEA did not have a timetable for banning or scheduling the drug, though some states have banned it.

To that end, users consider kratom a legal high, and it is easily purchased online. A 2010 study in the United Kingdom examined Web sites where kratom and many other quasilegal substances (including Salvia divinorum and legal precursors to LSD) could be purchased for an average of £10 (about $13 US currency).⁵ This study’s authors also noted a significant lack of product information on these marketplaces. As these products are not overseen by any regulatory body, the risk of overdose or adulteration is extremely high.^2,3,6-8 In fact, Krypton, a kratom product sold online, was found to be adulterated with O-desmethyltramadol—the active metabolite of the synthetic opiate tramadol—and implicated in at least nine deaths.⁷

This article presents a case of kratom abuse. It describes a brief history of the substance, its pharmacological characteristics, the clinical presentation of kratom abuse, and the treatment of kratom-related illness and evaluation of potential toxic sequelae. In light of the rapid proliferation of kratom in the United States, a basic working knowledge of the drug is quickly becoming a must for EPs.

Case Presentation

At his employer’s request, a 33-year-old man presented to his family physician for a worsening of his uncontrolled back pain from a herniated lumbar disk resulting from a motor vehicle collision 3 months before. At his physician’s office he stated, “I don’t care if I live or die, I’m tired of the pain,” and “I’m going to go off on somebody if I can’t get this pain under control.” He also endorsed having auditory hallucinations for several years and a history of violence and homicide. The problem arose precipitously after he became concerned that he was abusing his opioid medication, and it was discontinued. The patient was transferred to the local ED and admitted to the psychiatric service for his suicidal ideations and risk of harming self and others.

On admission to the psychiatric service, the patient complained of body aches, chills, rhinorrhea, and significantly worsened irritability from his baseline, consistent with opioid withdrawal. Initial point-of-care (POC) admission drug testing had been negative as had expanded urine tests looking for synthetic opioids, cannabinoids, and cathinones. The patient reported no opioid use but was unable to explain his current symptom patterns, which were worsening his chronic pain and hampering any attempt to build rapport. On hospital day 3, the patient’s opioid withdrawal resolved, and psychiatric treatment was able to progress fully. On hospital day 4, the inpatient treatment team received a message from the patient’s primary care manager stating that a friend of the patient had found a bottle of herbal pills in the patient’s car. This was later revealed to be a kratom formulation that he had purchased online.

Background

Kratom is the colloquial name of a tree that is native to Thailand, Malaysia, and other countries in Southeast Asia. These trees, which can grow to 50 feet high and 15 feet wide, have long been the source of herbal remedies in Southeast Asia.^2,3 The leaves of these trees contain psychoactive substances that have a variety of effects when consumed. At low doses, kratom causes a stimulant effect (akin to the leaves of the coca plant in South America); laborers and farmers often use it to help boost their energy. At higher doses, kratom causes an opioid-like effect, which at mega doses produces an intense euphoric state and has led to a steady growth in abuse worldwide. Although the government of Thailand banned the planting of Mitragyna speciosa as early as 1943, its continued proliferation in Southeast Asia and throughout the world has not ceased.^2,3,6

In the United Kingdom, kratom is currently the second most common drug that is considered a legal high, only behind salvia (Salvia divinorum), a hallucinogenic herb that is better known as a result of its use by young celebrities over the past decade.^5,8

Kratom can be taken in a variety of ways: Crushed leaves often are placed in gel caps and swallowed; it can be drunk as a tea, juice, or boiled syrup; and it can be smoked or insufflated.^2,3,5,6

Pharmacology and Clinical Presentation

More than 20 psychoactive compounds have been isolated from kratom. Although a discussion of all these compounds is beyond the scope of this review, the two major compounds are mitragynine and 7-hydroxymitragynine.

Mitragynine

Mitragynine, the most abundant psychoactive compound found in kratom, is an indole alkaloid (Figure 1). Extraction and analysis of this compound has demonstrated numerous effects on multiple receptors, including mu-, delta-, and kappa-opioid receptors, leading to its opioid-like effects, including analgesia and euphoria. Also similar to common opioids, withdrawal symptomatology can present after only 5 days of daily use. There is limited evidence that mitragynine can activate postsynaptic alpha-2 adrenergic receptors, which may act synergistically with the mu-agonist with regard to its analgesic effect.^2,5

7-Hydroxymitragynine

7-hydroxymitragynine, despite being far less concentrated in kratom preparations, is about 13 times more potent than morphine and 46 times more potent than mitragynine. It is thought that its hydroxyl side chain added to C7 (Figure 2) adds to its lipophilicity and ability to cross the blood-brain barrier at a far more rapid rate than that of mitragynine.²

Mitragynine and 7-hydroxymitragynine remain the best-studied psychoactive components of kratom at this time. Other compounds that have been isolated, such as speciociliatine, paynantheine, and speciogynine, may play a role in kratom’s analgesic and psychoactive effects. Animal studies have demonstrated antimuscarinic properties in these compounds, but the properties do not seem to have any demonstrable effect at the opioid receptors.²

Intoxication and Withdrawal

Due to its increasing worldwide popularity, it is now imperative for EPs to be aware of the presentation of patients with kratom abuse as well as the management of withdrawal in light of its dependence potential. However, large-scale studies have not been performed, and much of the evidence comes not from the medical literature but from Web sites such as Erowid or SageWisdom.^2,5-9 To that end, such information will be discussed along with the limited research and expert consensuses available in peer-reviewed medical literature.

Kratom seems to have dose-dependent effects. At low doses (1-5 g of raw crushed leaves), kratom abusers often report a mild energizing effect, thought to be secondary to the stimulant properties of kratom’s multiple alkaloids. Users have reported mild euphoria and highs similar to those of the abuse of methylphenidate or modafinil.^2,9,10 Also similar to abuse of those substances, users have reported anxiety, irritability, and aggressiveness as a result of the stimulant-like effects.

At moderate-to-high doses (5-15 g of raw crushed leaves), it is believed that the mu-opiate receptor agonism overtakes the stimulant effects, leading to the euphoria, relaxation, and analgesia seen with conventional opioid use and abuse.^2,10 In light of the drug’s substantial binding and agonism of all opioid receptors, constipation and itching also are seen.² As such, if an individual is intoxicated, he or she should be managed with supportive and symptomatic care and continuous monitoring of heart rate, blood pressure, respiratory rate, and oxygen saturation.^2,10 Kratom intoxication can precipitate psychotic episodes similar to those caused by opiate intoxication, so monitoring for agitation or psychotic behaviors is also indicated.^9,10

The medical management of a patient with an acute kratom overdose (typically requiring ingestion of >15 g of crushed leaves) begins with addressing airway support, breathing, and circulation along with continuous vital sign monitoring and laboratory testing, including POC glucose testing, complete blood count, electrolytes, lactate, venous blood gas, and measurable drug levels (ethanol, acetaminophen, tricyclic antidepressants, as indicated).¹¹ If it is determined that kratom was the intoxicant, the greatest concern of death is similar to that of opioid overdose: respiratory depression. Although there are no large-scale human studies demonstrating efficacy, multiple authors suggest the use of naloxone in kratom-related hypoventilation.^9,10

The development of dependence on kratom and its subsequent withdrawal phenomena are thought to be similar to that of opioids, in light of its strong mu agonism.^2,5,9,10 Indeed, kratom has a long history of being used by opioid-dependent patients as an attempt to quit drug abuse or stave off debilitating withdrawal symptoms when they are unable to acquire their substance of choice.^2,5-10 As such, withdrawal and the treatment thereof will also mimic that of opioid withdrawal.

The kratom-dependent individual will often present with rhinorrhea, lacrimation, dry mouth, hostility, aggression, and emotional lability similar to the case study described earlier.^2,9,10 Kratom withdrawal, much like intoxication, also may precipitate or worsen psychotic symptoms, and monitoring is necessary throughout the detoxification process.^2,5,10 Withdrawal management should proceed along ambulatory clinic or hospital opioid withdrawal protocols that include step-down administration of opioids or with nonopioid medications for symptomatic relief, including muscle relaxants, alpha-2 agonists, and antidiarrheal agents.^5,9,10

Kratom Toxicity

A review of the available medical literature has demonstrated a number of toxic effects with kratom abuse, either as the sole agent or in concert with prescribed medications, recreational coingestants, or as a result of manufacturer’s adulteration with other chemicals or drugs. Of particular interest to EPs are manic or psychotic episode precipitation, seizure, hypothyroidism, intrahepatic cholestatic injury, and even sudden cardiac death.^2,3,5-10 In addition to the basic history, physical, and laboratory examination, the workup of patients identified as kratom users should include the following:

• Fastidious medication reconciliation with drug-interaction check;
• Exhaustive substance abuse history;
• Identification of the brand name and source of kratom purchased, to determine whether there are advertised coingestants or reports of adulteration;
• Electrocardiogram;
• Thyroid function testing;
• Hepatic function testing; and
• Comprehensive neurological and mental status examinations.

In chronic users of kratom, a number of effects have been seen whose etiologies have not yet been determined. These effects include depression, anxiety, tremulousness, weight loss, and psychosis.^3-7 Additionally, a study by Kittirattanapaiboon et al¹² correlated drug use by those with concurrent mental health disorders (in particular, kratom, which was used in 59% of the ≥14,000 individuals included in the study sample) with statistically significant higher suicide risk.

Detection

Because kratom is a relatively new compound in the United States, medical and forensic laboratories are only now implementing kratom detection protocols. Many laboratories now use high-performance liquid chromatography to analyze for mitragynine, 7-hydroxymitragynine, and two metabolites of mitragynine in urine.⁷ Le et al¹³ were able to detect mitragynine in the urine in levels as low as 1 ng/mL, which is clinically useful as mitragynine has a half-life determined in animal studies to be 3.85 hours. Similar detection limits for mitragynine and 7-hydroxymitragynine are used only at the Naval Medical Center Portsmouth in Virginia; however, kratom was not detected in the case study patient’s urine because a urine test was not done until hospital day 5.

Case Conclusion

When gently confronted about the kratom found in his car, the case study patient admitted that he had purchased kratom online after he was “cut off” from prescription opioids for his pain. He admitted that although it was beneficial for his pain, he did notice worsening in his aggression toward his spouse and coworkers. This progressed to an exacerbation of his psychotic symptoms of hallucinations and persecutory delusions. These symptoms remained well hidden—but were present for years prior to his presentation at the hospital. The patient was discharged from the inpatient psychiatric unit on hospital day 16 with a diagnosis of schizoaffective disorder, depressive type in addition to opioid-use disorder. The patient agreed to seek a pain management specialist and discontinue kratom use.

Conclusion

Kratom is an emerging drug of abuse in the Western world. Although significant research is being conducted on its possible medical uses, little is known about kratom beyond the “trip reports” of kratom users posted online. Because of its technically legal status in the United States and multiple other Western countries, kratom is easily accessible. Emergency physicians need to be aware of kratom, and during their evaluations, question appropriate patients about kratom and other legal highs.

The vast majority of musculotendinous injuries occur secondary to violent contraction or excessive stretching.¹ Ligamentous injuries, on the other hand, are due to an abnormal motion of joints. The magnitude of inciting forces results in a spectrum of pathology, ranging from a minor tear to a complete disruption of structures.

Ultrasonography provides a detailed assessment of soft tissue anatomy and dynamic functionality, and in some instances can be comparable or even superior to magnetic resonance imaging² because the structural characteristics of certain tendons make them ideal for imaging via ultrasonography. We describe some of these characteristics and highlight their utility in diagnostic imaging.

Anatomical Structure

Tendons consist of tightly packed type I collagen fibers forming subfascicles that are arranged in a parallel distribution as fascicles. These bundles are held together by loose soft tissue, and the entire structure is covered by a thick fibroelastic epitendineum sheath. This linear distribution of structures yields a uniquely linear “fibrillary” pattern when viewed along the longitudinal axis of the structure (Figure 1a). In the short-axis view, the tendon appears as a well-circumscribed structure with speckled pattern of hyperechoic foci (Figure 1b). ³

Imaging Technique

The optimal scanning technique involves the use of a high-frequency linear transducer. Higher frequencies yield more detailed images, but may be limited in patients with deeper structures due to body habitus. A key concept in tendon evaluation is an artifact known as “anisotropy.” This refers to change in appearance of the tendon based on the incident angle of the ultrasound beam. For example, when the probe is held perpendicular to the structure of interest, parallel fibers will reflect the emitted beam toward the probe and thus appear as hyperechoic and speckled, a characteristic of these fibers (Figures 1a and 1b). Contrarily, if the probe is held at a nonperpendicular angle, the reflected beam will not return to the probe, resulting in a hypoechoic appearance (Figure 2).

Pathology

Tendon strains result in varying degrees of fibrous tearing. These tears can range from first-degree tears (a few fibers) to third-degree tears (complete disruption). Partial tears result in focal hematoma formation (Figure 3a) at the region of disruption, appearing on ultrasound as a hypoechoic fluid collection within a hyperechoic fibrillary or speckled tendon structure. If the disruption occurs along the surface of the tendon, a focus of anechoic fluid may be seen surrounding the tendon. Complete tendon ruptures, on the other hand, appear as a hypoechoic void with retracted tendon fragments visualized on either side⁴ (Figures 3b and 3c). Although complete tears can be more apparent clinically in areas in which a group of tendons performs a cohesive movement (ie, rotator cuff), ultrasound can significantly reduce the rate of delayed diagnosis when physical examination is equivocal.

In the appropriate clinical setting, ultrasonography can provide rapid and dynamic assessment of musculotendinous injuries. Lower extremity injuries, including those affecting the Achilles (Figure 1), quadriceps, (Figures 4a and 4b) and patellar tendons (Figure 5), are easier clinical applications.

Assessment of rotator cuff tendons, although more difficult, can provide a specific assessment of shoulder pain.⁵ In such scenarios, ultrasound can serve a very useful role as an adjunct to the physical examination.

Summary

Musculotendinous injuries many times present as nonspecific symptoms of pain and/or swelling. In the case of an equivocal physical examination, musculotendinous injuries can be diagnosed with increased accuracy through the use of ultrasound. Understanding the artifactual component of tendon ultrasound can aid the clinician in diagnosing these injuries, enhancing patient care and satisfaction.

The vast majority of musculotendinous injuries occur secondary to violent contraction or excessive stretching.¹ Ligamentous injuries, on the other hand, are due to an abnormal motion of joints. The magnitude of inciting forces results in a spectrum of pathology, ranging from a minor tear to a complete disruption of structures.

Ultrasonography provides a detailed assessment of soft tissue anatomy and dynamic functionality, and in some instances can be comparable or even superior to magnetic resonance imaging² because the structural characteristics of certain tendons make them ideal for imaging via ultrasonography. We describe some of these characteristics and highlight their utility in diagnostic imaging.

Anatomical Structure

Tendons consist of tightly packed type I collagen fibers forming subfascicles that are arranged in a parallel distribution as fascicles. These bundles are held together by loose soft tissue, and the entire structure is covered by a thick fibroelastic epitendineum sheath. This linear distribution of structures yields a uniquely linear “fibrillary” pattern when viewed along the longitudinal axis of the structure (Figure 1a). In the short-axis view, the tendon appears as a well-circumscribed structure with speckled pattern of hyperechoic foci (Figure 1b). ³

Imaging Technique

The optimal scanning technique involves the use of a high-frequency linear transducer. Higher frequencies yield more detailed images, but may be limited in patients with deeper structures due to body habitus. A key concept in tendon evaluation is an artifact known as “anisotropy.” This refers to change in appearance of the tendon based on the incident angle of the ultrasound beam. For example, when the probe is held perpendicular to the structure of interest, parallel fibers will reflect the emitted beam toward the probe and thus appear as hyperechoic and speckled, a characteristic of these fibers (Figures 1a and 1b). Contrarily, if the probe is held at a nonperpendicular angle, the reflected beam will not return to the probe, resulting in a hypoechoic appearance (Figure 2).

Pathology

Tendon strains result in varying degrees of fibrous tearing. These tears can range from first-degree tears (a few fibers) to third-degree tears (complete disruption). Partial tears result in focal hematoma formation (Figure 3a) at the region of disruption, appearing on ultrasound as a hypoechoic fluid collection within a hyperechoic fibrillary or speckled tendon structure. If the disruption occurs along the surface of the tendon, a focus of anechoic fluid may be seen surrounding the tendon. Complete tendon ruptures, on the other hand, appear as a hypoechoic void with retracted tendon fragments visualized on either side⁴ (Figures 3b and 3c). Although complete tears can be more apparent clinically in areas in which a group of tendons performs a cohesive movement (ie, rotator cuff), ultrasound can significantly reduce the rate of delayed diagnosis when physical examination is equivocal.

In the appropriate clinical setting, ultrasonography can provide rapid and dynamic assessment of musculotendinous injuries. Lower extremity injuries, including those affecting the Achilles (Figure 1), quadriceps, (Figures 4a and 4b) and patellar tendons (Figure 5), are easier clinical applications.

Assessment of rotator cuff tendons, although more difficult, can provide a specific assessment of shoulder pain.⁵ In such scenarios, ultrasound can serve a very useful role as an adjunct to the physical examination.

Summary

Musculotendinous injuries many times present as nonspecific symptoms of pain and/or swelling. In the case of an equivocal physical examination, musculotendinous injuries can be diagnosed with increased accuracy through the use of ultrasound. Understanding the artifactual component of tendon ultrasound can aid the clinician in diagnosing these injuries, enhancing patient care and satisfaction.

The vast majority of musculotendinous injuries occur secondary to violent contraction or excessive stretching.¹ Ligamentous injuries, on the other hand, are due to an abnormal motion of joints. The magnitude of inciting forces results in a spectrum of pathology, ranging from a minor tear to a complete disruption of structures.

Ultrasonography provides a detailed assessment of soft tissue anatomy and dynamic functionality, and in some instances can be comparable or even superior to magnetic resonance imaging² because the structural characteristics of certain tendons make them ideal for imaging via ultrasonography. We describe some of these characteristics and highlight their utility in diagnostic imaging.

Anatomical Structure

Tendons consist of tightly packed type I collagen fibers forming subfascicles that are arranged in a parallel distribution as fascicles. These bundles are held together by loose soft tissue, and the entire structure is covered by a thick fibroelastic epitendineum sheath. This linear distribution of structures yields a uniquely linear “fibrillary” pattern when viewed along the longitudinal axis of the structure (Figure 1a). In the short-axis view, the tendon appears as a well-circumscribed structure with speckled pattern of hyperechoic foci (Figure 1b). ³

Imaging Technique

The optimal scanning technique involves the use of a high-frequency linear transducer. Higher frequencies yield more detailed images, but may be limited in patients with deeper structures due to body habitus. A key concept in tendon evaluation is an artifact known as “anisotropy.” This refers to change in appearance of the tendon based on the incident angle of the ultrasound beam. For example, when the probe is held perpendicular to the structure of interest, parallel fibers will reflect the emitted beam toward the probe and thus appear as hyperechoic and speckled, a characteristic of these fibers (Figures 1a and 1b). Contrarily, if the probe is held at a nonperpendicular angle, the reflected beam will not return to the probe, resulting in a hypoechoic appearance (Figure 2).

Pathology

Tendon strains result in varying degrees of fibrous tearing. These tears can range from first-degree tears (a few fibers) to third-degree tears (complete disruption). Partial tears result in focal hematoma formation (Figure 3a) at the region of disruption, appearing on ultrasound as a hypoechoic fluid collection within a hyperechoic fibrillary or speckled tendon structure. If the disruption occurs along the surface of the tendon, a focus of anechoic fluid may be seen surrounding the tendon. Complete tendon ruptures, on the other hand, appear as a hypoechoic void with retracted tendon fragments visualized on either side⁴ (Figures 3b and 3c). Although complete tears can be more apparent clinically in areas in which a group of tendons performs a cohesive movement (ie, rotator cuff), ultrasound can significantly reduce the rate of delayed diagnosis when physical examination is equivocal.

In the appropriate clinical setting, ultrasonography can provide rapid and dynamic assessment of musculotendinous injuries. Lower extremity injuries, including those affecting the Achilles (Figure 1), quadriceps, (Figures 4a and 4b) and patellar tendons (Figure 5), are easier clinical applications.

Assessment of rotator cuff tendons, although more difficult, can provide a specific assessment of shoulder pain.⁵ In such scenarios, ultrasound can serve a very useful role as an adjunct to the physical examination.

Summary

Musculotendinous injuries many times present as nonspecific symptoms of pain and/or swelling. In the case of an equivocal physical examination, musculotendinous injuries can be diagnosed with increased accuracy through the use of ultrasound. Understanding the artifactual component of tendon ultrasound can aid the clinician in diagnosing these injuries, enhancing patient care and satisfaction.

In a historic collaboration, 10 major emergency medicine organizations have joined forces to create The Coalition to Oppose Medical Merit Badges (COMMB). In its news release, the Coalition stated it “…believes that board-certified emergency physicians who actively maintain their board certification should not be required to complete short-course certification or acquire condition-specific continuing medical education credits in advanced resuscitation, trauma care, stroke care, cardiovascular care, procedural sedation, or pediatric care in order to obtain or maintain medical staff privileges to work in an emergency department.”

The COMMB consists of the American Academy of Emergency Medicine (AAEM), American Academy of Emergency Medicine/Resident and Student Association (AAEM/RSA), American Board of Emergency Medicine (ABEM), American College of Emergency Physicians (ACEP), Association of Academic Chairs of Emergency Medicine (AACEM), Council of Emergency Medicine Residency Directors (CORD), Emergency Medicine Residents’ Association (EMRA), Society for Academic Emergency Medicine (SAEM), American Osteopathic Board of Emergency Medicine (AOBEM), and American College of Osteopathic Emergency Physicians (ACOEP).

In a written statement signed by the president/chair of each member organization, COMMB further asserted:

Similarly, mandatory targeted continuing medical education (CME) requirements do not offer any meaningful value for the public or for the emergency physician who has achieved and maintained board certification. Such requirements are often promulgated by others who incompletely understand the foundation of knowledge and skills acquired by successfully completing an Accreditation Council for Graduate Medical Education-accredited or American Osteopathic Association-approved Emergency Medicine Residency Program. These “merit badges” add no additional value for board-certified emergency physicians. Instead, they devalue the board certification process, failing to recognize the rigor of the ABEM Maintenance of Certification (MOC) Program. In essence, medical merit badges set a lower bar than a diplomate’s education, training, and ongoing learning, as measured by initial board certification and maintenance of certification.

The Coalition finds no rational justification to require medical merit badges for board-certified emergency physicians who maintain their board certification. Our committed professional organizations provide the best opportunities for continuous professional development and medical merit badges dismiss the quality of those educational efforts.

Opposing the requirements for medical merit badges will be a long and challenging struggle. It will take time to help administrators and regulatory bodies to better understand the rigorous standards to which we adhere as board-certified emergency physicians. In the coming months, we will develop our long-term strategy to create success and a pathway to recognize clinical excellence. We welcome your thoughts and suggestions as to how we can best succeed. In the near future, we will ask for strong support and a loud and unified voice.

We will persist and we are up to the challenge—we are board-certified emergency physicians. Opposing medical merit badges is the right thing to do for our specialty. We will forever demonstrate a lifelong commitment to caring for anyone who is ill or injured, at any time, for any reason.

Study Nixed Magnesium for Infants With Acute Bronchiolitis

AMY KARON

FRONTLINE MEDICAL news

Intravenous (IV) magnesium does not benefit, and may harm, infants with moderate-to-severe acute bronchiolitis, investigators reported. Compared with placebo, adding a single IV dose of magnesium sulfate (100 mg/kg) to usual care did not reduce time to medical readiness for discharge, even when patients had eczema or a family history of asthma, and was tied to a more than 3-fold rise in the rate of short-term readmissions, Khalid Al Ansari, MD, of Hamad Medical Corp in Doha, Qatar, and his associates wrote in Chest. “To our knowledge, this is the first randomized study to investigate the effect of intravenous magnesium in a bronchiolitis population,” they added.

Bronchiolitis lacks new, inexpensive, readily available treatments, despite being a common reason for hospital admission, the researchers noted. For older children with moderate-to-severe exacerbations of asthma, a meta-analysis found that the addition of magnesium to usual care appeared to cut readmissions and shorten lengths of stay, compared with placebo. To explore magnesium therapy in younger children, the investigators enrolled 162 previously healthy infants up to 18 months old who had been admitted to the short-stay unit of a pediatric emergency center with a diagnosis of moderate-to-severe viral bronchiolitis. Patients received usual care with oral dexamethasone and nebulized 5% hypertonic saline in 1 mL of 1:1000 epinephrine, plus a 60-minute IV infusion with a blinded syringe of either 0.9% saline placebo or magnesium sulfate (100 mg/kg).

The primary endpoint, time to medical readiness for discharge, did not statistically differ between groups, averaging 24.1 (95% confidence interval [CI], 20.0-29.1) hours with magnesium and 25.3 (95% CI, 20.3-31.5) hours with placebo (P = .91). Among patients with a history of eczema or a family history of asthma, mean times to readiness for discharge resembled those for the entire cohort and did not statistically differ based on treatment. Average Wang bronchiolitis severity scores also were similar between groups, as were rates of outpatient clinic visits (33.8% with magnesium and 27.2% with placebo). Thus, the trial identified “no benefit in adding intravenous magnesium for infant bronchiolitis, even in patients characterized to be at a higher risk for asthma,” the researchers concluded.

Strikingly, 2-week readmission rates were 19.5% with magnesium (95% CI, 11.3-30.1) and 6.2% with placebo (95% CI, 0.02-13.8; P = .016). Among patients with eczema or a family history of asthma, 2-week readmission rates also were significantly higher with magnesium (26.3%; 95% CI, 13.4-43.1) than with placebo (7.5%; 95% CI, 1.6-20.4; P = .034) These might have been chance findings, or magnesium might have masked worse bronchiolitis, prolonged the disease course, or interacted with 5% hypertonic saline or systemic corticosteroids, the investigators said. Intravenous magnesium might contribute to secondary relapse, especially among patients with eczema or a family history of asthma, they added.

Patients in this study had a median age of 3.7 months (range, 22 days to 17.6 months), about half had eczema or a family history of asthma, and 86% had positive nasopharyngeal virus swabs. Cardiopulmonary monitoring revealed no acute events during treatment. Of 16 readmissions in the magnesium group, 11 entered the infirmary and four entered the hospital. The five placebo readmissions included four to the infirmary and one to the hospital.

“As with other ‘negative studies,’ we may have failed to identify a benefit from intravenous magnesium in a patient subgroup because of our limited sample size,” the investigators wrote. “But we think our findings are generalizable to a similarly heterogeneous group of patients presenting for bronchiolitis care in a busy urban emergency department.”

Alansari K, Sayyed R, Davidson BL, Al Jawala S, Ghadier M. Intravenous magnesium sulfate for bronchiolitis: A randomized trial. Chest. 2017;pii:S0012-3692(17):30361-30366. doi:10.1016/j.chest.2017.03.002. [Epub ahead of print]

CDC: Some Shigella Strains Show Reduced Ciprofloxacin Susceptibility

SHARON WORCESTER

FRONTLINE MEDICAL NEWS

The Centers for Disease Control and Prevention (CDC) has identified an increase in Shigella isolates with reduced susceptibility to ciprofloxacin, and has released an official health advisory outlining new recommendations for clinical diagnosis, management, and reporting, as well as for laboratories and public health officials.

The Shigella isolates of concern in the United States have minimum inhibitory concentration (MIC) values of 0.12-1 mcg/mL for ciprofloxacin, which is within the range considered susceptible. These strains, however, “often have a quinolone resistance gene that may lead to clinically significant reduced susceptibility to fluoroquinolone antibiotics,” such as ciprofloxacin, according to the CDC advisory.

It is possible that strains with MIC in the 0.12-1 mcg/mL range may have worse clinical outcome or increased risk of transmission, so the CDC made the following recommendations to clinicians:

• Order a stool culture to obtain isolates for antimicrobial susceptibility testing in suspected cases.
• Order antimicrobial susceptibility testing when ordering a stool culture for Shigella.
• Avoid routine prescribing of antibiotic therapy for Shigella infection, instead reserving antibiotics for patients with a clinical indication or when advised by public health officials in an outbreak setting.
• Tailor antibiotic choice (when antibiotics are indicated) to susceptibility results as soon as possible—with special attention given to the MIC for fluoroquinolone antibiotics.
• Obtain follow-up stool cultures in shigellosis patients who have continued or worsening symptoms despite antibiotic therapy.
• Consult local or state health departments for guidance on when patients may return to childcare, school, or work.
• Counsel patients with active diarrhea on how they can prevent spreading the infection to others, regardless of whether antibiotic treatment is prescribed.

Additionally, the CDC noted that shigellosis is a nationally notifiable condition, and all cases should be reported to one’s local health department. If a patient with shigellosis and a ciprofloxacin MIC of 0.12-1 mcg/mL is identified, this information should be included in the report to facilitate further testing of the isolate.

The CDC reported that it is working with state and local public health departments and clinical partners to determine if outcomes are indeed worse for patients treated with ciprofloxacin for Shigella strains harboring a quinolone resistance gene, and it will continue to monitor trends in susceptibility of Shigella isolates and to perform genetic testing on select strains to confirm the presence and type of resistance genes.

Prenotification, Unequivocal Stroke Promote Ultrafast Door-to-Needle Time

SHARON WORCESTER

FRONTLINE MEDICAL NEWS

Ultrafast door-to-needle times (DNTs) of 10 minutes or less for IV acute ischemic stroke thrombolysis can be safely achieved in carefully selected cases, according to a review of cases at an Austrian teaching hospital.

Raffi Topakian, MD, and his colleagues at the Academic Teaching Hospital Wels-Grieskirchen in Wels, Austria, followed a multidisciplinary intervention to reinforce key components of the well-known Helsinki model of acute stroke care to improve the IV thrombolysis rate and the median DNT at the teaching hospital, and analyzed data from 361 patients who underwent intravenous thrombolysis (IVT) for stroke there between July 2014 and September 2016. The IVT rate increased from 19% to about 27% after intervention, and the DNT during the study period was 60 minutes or less in 316 patients (87.5%), 30 minutes or less in 181 patients (50.1%), and 10 minutes or less in 63 patients (17.5%).

“Over the study period, we reduced the DNT time from 49 minutes to 25 minutes. This was significant, and the door-to-needle times were astonishingly similar for the in-hours service and the out-of-hour service,” he said at the annual meeting of the American Academy of Neurology.

Further, the rate of prenotifications from emergency medical services (EMS) rose from about 30% to 63% during the study period.

Patients with ultrafast DNT vs those with slower DNT were older, had more chronic heart failure, had more severe stroke (National Institutes of Health Stroke Scale score of 10 vs 5), had more anterior circulation stroke and cardioembolic stroke, and had clear onset of stroke. Independent predictors of ultrafast DNT included prenotification by EMS, anterior circulation syndrome, chronic heart failure, and having a stroke neurologist on duty, Dr Topakian said.

“Ultrashort DNTs can be achieved safely. The key is that we are prenotified by the EMS, that we can get all the relevant history details during transport, that there is a dedicated multidisciplinary stroke team and EMS staff, and that we have a seemingly unequivocal clinical scenario,” he said. “Out-of-hours DNT matched in-hours DNT, but the caveat is we’re talking about highly selected candidates; safety must not be sacrificed for the sake of speed, in all of our patients.”

In a historic collaboration, 10 major emergency medicine organizations have joined forces to create The Coalition to Oppose Medical Merit Badges (COMMB). In its news release, the Coalition stated it “…believes that board-certified emergency physicians who actively maintain their board certification should not be required to complete short-course certification or acquire condition-specific continuing medical education credits in advanced resuscitation, trauma care, stroke care, cardiovascular care, procedural sedation, or pediatric care in order to obtain or maintain medical staff privileges to work in an emergency department.”

The COMMB consists of the American Academy of Emergency Medicine (AAEM), American Academy of Emergency Medicine/Resident and Student Association (AAEM/RSA), American Board of Emergency Medicine (ABEM), American College of Emergency Physicians (ACEP), Association of Academic Chairs of Emergency Medicine (AACEM), Council of Emergency Medicine Residency Directors (CORD), Emergency Medicine Residents’ Association (EMRA), Society for Academic Emergency Medicine (SAEM), American Osteopathic Board of Emergency Medicine (AOBEM), and American College of Osteopathic Emergency Physicians (ACOEP).

In a written statement signed by the president/chair of each member organization, COMMB further asserted:

Similarly, mandatory targeted continuing medical education (CME) requirements do not offer any meaningful value for the public or for the emergency physician who has achieved and maintained board certification. Such requirements are often promulgated by others who incompletely understand the foundation of knowledge and skills acquired by successfully completing an Accreditation Council for Graduate Medical Education-accredited or American Osteopathic Association-approved Emergency Medicine Residency Program. These “merit badges” add no additional value for board-certified emergency physicians. Instead, they devalue the board certification process, failing to recognize the rigor of the ABEM Maintenance of Certification (MOC) Program. In essence, medical merit badges set a lower bar than a diplomate’s education, training, and ongoing learning, as measured by initial board certification and maintenance of certification.

The Coalition finds no rational justification to require medical merit badges for board-certified emergency physicians who maintain their board certification. Our committed professional organizations provide the best opportunities for continuous professional development and medical merit badges dismiss the quality of those educational efforts.

Opposing the requirements for medical merit badges will be a long and challenging struggle. It will take time to help administrators and regulatory bodies to better understand the rigorous standards to which we adhere as board-certified emergency physicians. In the coming months, we will develop our long-term strategy to create success and a pathway to recognize clinical excellence. We welcome your thoughts and suggestions as to how we can best succeed. In the near future, we will ask for strong support and a loud and unified voice.

We will persist and we are up to the challenge—we are board-certified emergency physicians. Opposing medical merit badges is the right thing to do for our specialty. We will forever demonstrate a lifelong commitment to caring for anyone who is ill or injured, at any time, for any reason.

Study Nixed Magnesium for Infants With Acute Bronchiolitis

AMY KARON

FRONTLINE MEDICAL news

Intravenous (IV) magnesium does not benefit, and may harm, infants with moderate-to-severe acute bronchiolitis, investigators reported. Compared with placebo, adding a single IV dose of magnesium sulfate (100 mg/kg) to usual care did not reduce time to medical readiness for discharge, even when patients had eczema or a family history of asthma, and was tied to a more than 3-fold rise in the rate of short-term readmissions, Khalid Al Ansari, MD, of Hamad Medical Corp in Doha, Qatar, and his associates wrote in Chest. “To our knowledge, this is the first randomized study to investigate the effect of intravenous magnesium in a bronchiolitis population,” they added.

Bronchiolitis lacks new, inexpensive, readily available treatments, despite being a common reason for hospital admission, the researchers noted. For older children with moderate-to-severe exacerbations of asthma, a meta-analysis found that the addition of magnesium to usual care appeared to cut readmissions and shorten lengths of stay, compared with placebo. To explore magnesium therapy in younger children, the investigators enrolled 162 previously healthy infants up to 18 months old who had been admitted to the short-stay unit of a pediatric emergency center with a diagnosis of moderate-to-severe viral bronchiolitis. Patients received usual care with oral dexamethasone and nebulized 5% hypertonic saline in 1 mL of 1:1000 epinephrine, plus a 60-minute IV infusion with a blinded syringe of either 0.9% saline placebo or magnesium sulfate (100 mg/kg).

The primary endpoint, time to medical readiness for discharge, did not statistically differ between groups, averaging 24.1 (95% confidence interval [CI], 20.0-29.1) hours with magnesium and 25.3 (95% CI, 20.3-31.5) hours with placebo (P = .91). Among patients with a history of eczema or a family history of asthma, mean times to readiness for discharge resembled those for the entire cohort and did not statistically differ based on treatment. Average Wang bronchiolitis severity scores also were similar between groups, as were rates of outpatient clinic visits (33.8% with magnesium and 27.2% with placebo). Thus, the trial identified “no benefit in adding intravenous magnesium for infant bronchiolitis, even in patients characterized to be at a higher risk for asthma,” the researchers concluded.

Strikingly, 2-week readmission rates were 19.5% with magnesium (95% CI, 11.3-30.1) and 6.2% with placebo (95% CI, 0.02-13.8; P = .016). Among patients with eczema or a family history of asthma, 2-week readmission rates also were significantly higher with magnesium (26.3%; 95% CI, 13.4-43.1) than with placebo (7.5%; 95% CI, 1.6-20.4; P = .034) These might have been chance findings, or magnesium might have masked worse bronchiolitis, prolonged the disease course, or interacted with 5% hypertonic saline or systemic corticosteroids, the investigators said. Intravenous magnesium might contribute to secondary relapse, especially among patients with eczema or a family history of asthma, they added.

Patients in this study had a median age of 3.7 months (range, 22 days to 17.6 months), about half had eczema or a family history of asthma, and 86% had positive nasopharyngeal virus swabs. Cardiopulmonary monitoring revealed no acute events during treatment. Of 16 readmissions in the magnesium group, 11 entered the infirmary and four entered the hospital. The five placebo readmissions included four to the infirmary and one to the hospital.

“As with other ‘negative studies,’ we may have failed to identify a benefit from intravenous magnesium in a patient subgroup because of our limited sample size,” the investigators wrote. “But we think our findings are generalizable to a similarly heterogeneous group of patients presenting for bronchiolitis care in a busy urban emergency department.”

Alansari K, Sayyed R, Davidson BL, Al Jawala S, Ghadier M. Intravenous magnesium sulfate for bronchiolitis: A randomized trial. Chest. 2017;pii:S0012-3692(17):30361-30366. doi:10.1016/j.chest.2017.03.002. [Epub ahead of print]

CDC: Some Shigella Strains Show Reduced Ciprofloxacin Susceptibility

SHARON WORCESTER

FRONTLINE MEDICAL NEWS

The Centers for Disease Control and Prevention (CDC) has identified an increase in Shigella isolates with reduced susceptibility to ciprofloxacin, and has released an official health advisory outlining new recommendations for clinical diagnosis, management, and reporting, as well as for laboratories and public health officials.

The Shigella isolates of concern in the United States have minimum inhibitory concentration (MIC) values of 0.12-1 mcg/mL for ciprofloxacin, which is within the range considered susceptible. These strains, however, “often have a quinolone resistance gene that may lead to clinically significant reduced susceptibility to fluoroquinolone antibiotics,” such as ciprofloxacin, according to the CDC advisory.

It is possible that strains with MIC in the 0.12-1 mcg/mL range may have worse clinical outcome or increased risk of transmission, so the CDC made the following recommendations to clinicians:

• Order a stool culture to obtain isolates for antimicrobial susceptibility testing in suspected cases.
• Order antimicrobial susceptibility testing when ordering a stool culture for Shigella.
• Avoid routine prescribing of antibiotic therapy for Shigella infection, instead reserving antibiotics for patients with a clinical indication or when advised by public health officials in an outbreak setting.
• Tailor antibiotic choice (when antibiotics are indicated) to susceptibility results as soon as possible—with special attention given to the MIC for fluoroquinolone antibiotics.
• Obtain follow-up stool cultures in shigellosis patients who have continued or worsening symptoms despite antibiotic therapy.
• Consult local or state health departments for guidance on when patients may return to childcare, school, or work.
• Counsel patients with active diarrhea on how they can prevent spreading the infection to others, regardless of whether antibiotic treatment is prescribed.

Additionally, the CDC noted that shigellosis is a nationally notifiable condition, and all cases should be reported to one’s local health department. If a patient with shigellosis and a ciprofloxacin MIC of 0.12-1 mcg/mL is identified, this information should be included in the report to facilitate further testing of the isolate.

The CDC reported that it is working with state and local public health departments and clinical partners to determine if outcomes are indeed worse for patients treated with ciprofloxacin for Shigella strains harboring a quinolone resistance gene, and it will continue to monitor trends in susceptibility of Shigella isolates and to perform genetic testing on select strains to confirm the presence and type of resistance genes.

Prenotification, Unequivocal Stroke Promote Ultrafast Door-to-Needle Time

SHARON WORCESTER

FRONTLINE MEDICAL NEWS

Ultrafast door-to-needle times (DNTs) of 10 minutes or less for IV acute ischemic stroke thrombolysis can be safely achieved in carefully selected cases, according to a review of cases at an Austrian teaching hospital.

Raffi Topakian, MD, and his colleagues at the Academic Teaching Hospital Wels-Grieskirchen in Wels, Austria, followed a multidisciplinary intervention to reinforce key components of the well-known Helsinki model of acute stroke care to improve the IV thrombolysis rate and the median DNT at the teaching hospital, and analyzed data from 361 patients who underwent intravenous thrombolysis (IVT) for stroke there between July 2014 and September 2016. The IVT rate increased from 19% to about 27% after intervention, and the DNT during the study period was 60 minutes or less in 316 patients (87.5%), 30 minutes or less in 181 patients (50.1%), and 10 minutes or less in 63 patients (17.5%).

“Over the study period, we reduced the DNT time from 49 minutes to 25 minutes. This was significant, and the door-to-needle times were astonishingly similar for the in-hours service and the out-of-hour service,” he said at the annual meeting of the American Academy of Neurology.

Further, the rate of prenotifications from emergency medical services (EMS) rose from about 30% to 63% during the study period.

Patients with ultrafast DNT vs those with slower DNT were older, had more chronic heart failure, had more severe stroke (National Institutes of Health Stroke Scale score of 10 vs 5), had more anterior circulation stroke and cardioembolic stroke, and had clear onset of stroke. Independent predictors of ultrafast DNT included prenotification by EMS, anterior circulation syndrome, chronic heart failure, and having a stroke neurologist on duty, Dr Topakian said.

“Ultrashort DNTs can be achieved safely. The key is that we are prenotified by the EMS, that we can get all the relevant history details during transport, that there is a dedicated multidisciplinary stroke team and EMS staff, and that we have a seemingly unequivocal clinical scenario,” he said. “Out-of-hours DNT matched in-hours DNT, but the caveat is we’re talking about highly selected candidates; safety must not be sacrificed for the sake of speed, in all of our patients.”

In a historic collaboration, 10 major emergency medicine organizations have joined forces to create The Coalition to Oppose Medical Merit Badges (COMMB). In its news release, the Coalition stated it “…believes that board-certified emergency physicians who actively maintain their board certification should not be required to complete short-course certification or acquire condition-specific continuing medical education credits in advanced resuscitation, trauma care, stroke care, cardiovascular care, procedural sedation, or pediatric care in order to obtain or maintain medical staff privileges to work in an emergency department.”

The COMMB consists of the American Academy of Emergency Medicine (AAEM), American Academy of Emergency Medicine/Resident and Student Association (AAEM/RSA), American Board of Emergency Medicine (ABEM), American College of Emergency Physicians (ACEP), Association of Academic Chairs of Emergency Medicine (AACEM), Council of Emergency Medicine Residency Directors (CORD), Emergency Medicine Residents’ Association (EMRA), Society for Academic Emergency Medicine (SAEM), American Osteopathic Board of Emergency Medicine (AOBEM), and American College of Osteopathic Emergency Physicians (ACOEP).

In a written statement signed by the president/chair of each member organization, COMMB further asserted:

Similarly, mandatory targeted continuing medical education (CME) requirements do not offer any meaningful value for the public or for the emergency physician who has achieved and maintained board certification. Such requirements are often promulgated by others who incompletely understand the foundation of knowledge and skills acquired by successfully completing an Accreditation Council for Graduate Medical Education-accredited or American Osteopathic Association-approved Emergency Medicine Residency Program. These “merit badges” add no additional value for board-certified emergency physicians. Instead, they devalue the board certification process, failing to recognize the rigor of the ABEM Maintenance of Certification (MOC) Program. In essence, medical merit badges set a lower bar than a diplomate’s education, training, and ongoing learning, as measured by initial board certification and maintenance of certification.

The Coalition finds no rational justification to require medical merit badges for board-certified emergency physicians who maintain their board certification. Our committed professional organizations provide the best opportunities for continuous professional development and medical merit badges dismiss the quality of those educational efforts.

Opposing the requirements for medical merit badges will be a long and challenging struggle. It will take time to help administrators and regulatory bodies to better understand the rigorous standards to which we adhere as board-certified emergency physicians. In the coming months, we will develop our long-term strategy to create success and a pathway to recognize clinical excellence. We welcome your thoughts and suggestions as to how we can best succeed. In the near future, we will ask for strong support and a loud and unified voice.

We will persist and we are up to the challenge—we are board-certified emergency physicians. Opposing medical merit badges is the right thing to do for our specialty. We will forever demonstrate a lifelong commitment to caring for anyone who is ill or injured, at any time, for any reason.

Study Nixed Magnesium for Infants With Acute Bronchiolitis

AMY KARON

FRONTLINE MEDICAL news

Intravenous (IV) magnesium does not benefit, and may harm, infants with moderate-to-severe acute bronchiolitis, investigators reported. Compared with placebo, adding a single IV dose of magnesium sulfate (100 mg/kg) to usual care did not reduce time to medical readiness for discharge, even when patients had eczema or a family history of asthma, and was tied to a more than 3-fold rise in the rate of short-term readmissions, Khalid Al Ansari, MD, of Hamad Medical Corp in Doha, Qatar, and his associates wrote in Chest. “To our knowledge, this is the first randomized study to investigate the effect of intravenous magnesium in a bronchiolitis population,” they added.

Bronchiolitis lacks new, inexpensive, readily available treatments, despite being a common reason for hospital admission, the researchers noted. For older children with moderate-to-severe exacerbations of asthma, a meta-analysis found that the addition of magnesium to usual care appeared to cut readmissions and shorten lengths of stay, compared with placebo. To explore magnesium therapy in younger children, the investigators enrolled 162 previously healthy infants up to 18 months old who had been admitted to the short-stay unit of a pediatric emergency center with a diagnosis of moderate-to-severe viral bronchiolitis. Patients received usual care with oral dexamethasone and nebulized 5% hypertonic saline in 1 mL of 1:1000 epinephrine, plus a 60-minute IV infusion with a blinded syringe of either 0.9% saline placebo or magnesium sulfate (100 mg/kg).

The primary endpoint, time to medical readiness for discharge, did not statistically differ between groups, averaging 24.1 (95% confidence interval [CI], 20.0-29.1) hours with magnesium and 25.3 (95% CI, 20.3-31.5) hours with placebo (P = .91). Among patients with a history of eczema or a family history of asthma, mean times to readiness for discharge resembled those for the entire cohort and did not statistically differ based on treatment. Average Wang bronchiolitis severity scores also were similar between groups, as were rates of outpatient clinic visits (33.8% with magnesium and 27.2% with placebo). Thus, the trial identified “no benefit in adding intravenous magnesium for infant bronchiolitis, even in patients characterized to be at a higher risk for asthma,” the researchers concluded.

Strikingly, 2-week readmission rates were 19.5% with magnesium (95% CI, 11.3-30.1) and 6.2% with placebo (95% CI, 0.02-13.8; P = .016). Among patients with eczema or a family history of asthma, 2-week readmission rates also were significantly higher with magnesium (26.3%; 95% CI, 13.4-43.1) than with placebo (7.5%; 95% CI, 1.6-20.4; P = .034) These might have been chance findings, or magnesium might have masked worse bronchiolitis, prolonged the disease course, or interacted with 5% hypertonic saline or systemic corticosteroids, the investigators said. Intravenous magnesium might contribute to secondary relapse, especially among patients with eczema or a family history of asthma, they added.

Patients in this study had a median age of 3.7 months (range, 22 days to 17.6 months), about half had eczema or a family history of asthma, and 86% had positive nasopharyngeal virus swabs. Cardiopulmonary monitoring revealed no acute events during treatment. Of 16 readmissions in the magnesium group, 11 entered the infirmary and four entered the hospital. The five placebo readmissions included four to the infirmary and one to the hospital.

“As with other ‘negative studies,’ we may have failed to identify a benefit from intravenous magnesium in a patient subgroup because of our limited sample size,” the investigators wrote. “But we think our findings are generalizable to a similarly heterogeneous group of patients presenting for bronchiolitis care in a busy urban emergency department.”

Alansari K, Sayyed R, Davidson BL, Al Jawala S, Ghadier M. Intravenous magnesium sulfate for bronchiolitis: A randomized trial. Chest. 2017;pii:S0012-3692(17):30361-30366. doi:10.1016/j.chest.2017.03.002. [Epub ahead of print]

CDC: Some Shigella Strains Show Reduced Ciprofloxacin Susceptibility

SHARON WORCESTER

FRONTLINE MEDICAL NEWS

The Centers for Disease Control and Prevention (CDC) has identified an increase in Shigella isolates with reduced susceptibility to ciprofloxacin, and has released an official health advisory outlining new recommendations for clinical diagnosis, management, and reporting, as well as for laboratories and public health officials.

The Shigella isolates of concern in the United States have minimum inhibitory concentration (MIC) values of 0.12-1 mcg/mL for ciprofloxacin, which is within the range considered susceptible. These strains, however, “often have a quinolone resistance gene that may lead to clinically significant reduced susceptibility to fluoroquinolone antibiotics,” such as ciprofloxacin, according to the CDC advisory.

It is possible that strains with MIC in the 0.12-1 mcg/mL range may have worse clinical outcome or increased risk of transmission, so the CDC made the following recommendations to clinicians:

• Order a stool culture to obtain isolates for antimicrobial susceptibility testing in suspected cases.
• Order antimicrobial susceptibility testing when ordering a stool culture for Shigella.
• Avoid routine prescribing of antibiotic therapy for Shigella infection, instead reserving antibiotics for patients with a clinical indication or when advised by public health officials in an outbreak setting.
• Tailor antibiotic choice (when antibiotics are indicated) to susceptibility results as soon as possible—with special attention given to the MIC for fluoroquinolone antibiotics.
• Obtain follow-up stool cultures in shigellosis patients who have continued or worsening symptoms despite antibiotic therapy.
• Consult local or state health departments for guidance on when patients may return to childcare, school, or work.
• Counsel patients with active diarrhea on how they can prevent spreading the infection to others, regardless of whether antibiotic treatment is prescribed.

Additionally, the CDC noted that shigellosis is a nationally notifiable condition, and all cases should be reported to one’s local health department. If a patient with shigellosis and a ciprofloxacin MIC of 0.12-1 mcg/mL is identified, this information should be included in the report to facilitate further testing of the isolate.

The CDC reported that it is working with state and local public health departments and clinical partners to determine if outcomes are indeed worse for patients treated with ciprofloxacin for Shigella strains harboring a quinolone resistance gene, and it will continue to monitor trends in susceptibility of Shigella isolates and to perform genetic testing on select strains to confirm the presence and type of resistance genes.

Prenotification, Unequivocal Stroke Promote Ultrafast Door-to-Needle Time

SHARON WORCESTER

FRONTLINE MEDICAL NEWS

Ultrafast door-to-needle times (DNTs) of 10 minutes or less for IV acute ischemic stroke thrombolysis can be safely achieved in carefully selected cases, according to a review of cases at an Austrian teaching hospital.

Raffi Topakian, MD, and his colleagues at the Academic Teaching Hospital Wels-Grieskirchen in Wels, Austria, followed a multidisciplinary intervention to reinforce key components of the well-known Helsinki model of acute stroke care to improve the IV thrombolysis rate and the median DNT at the teaching hospital, and analyzed data from 361 patients who underwent intravenous thrombolysis (IVT) for stroke there between July 2014 and September 2016. The IVT rate increased from 19% to about 27% after intervention, and the DNT during the study period was 60 minutes or less in 316 patients (87.5%), 30 minutes or less in 181 patients (50.1%), and 10 minutes or less in 63 patients (17.5%).

“Over the study period, we reduced the DNT time from 49 minutes to 25 minutes. This was significant, and the door-to-needle times were astonishingly similar for the in-hours service and the out-of-hour service,” he said at the annual meeting of the American Academy of Neurology.

Further, the rate of prenotifications from emergency medical services (EMS) rose from about 30% to 63% during the study period.

Patients with ultrafast DNT vs those with slower DNT were older, had more chronic heart failure, had more severe stroke (National Institutes of Health Stroke Scale score of 10 vs 5), had more anterior circulation stroke and cardioembolic stroke, and had clear onset of stroke. Independent predictors of ultrafast DNT included prenotification by EMS, anterior circulation syndrome, chronic heart failure, and having a stroke neurologist on duty, Dr Topakian said.

“Ultrashort DNTs can be achieved safely. The key is that we are prenotified by the EMS, that we can get all the relevant history details during transport, that there is a dedicated multidisciplinary stroke team and EMS staff, and that we have a seemingly unequivocal clinical scenario,” he said. “Out-of-hours DNT matched in-hours DNT, but the caveat is we’re talking about highly selected candidates; safety must not be sacrificed for the sake of speed, in all of our patients.”

MONTREAL – Clinicians who manage the care of children with newly diagnosed idiopathic thrombocytopenic purpura (ITP) have to decide whether to treat patients early and possibly increase risk for chronic ITP down the road or to leave well enough alone and treat only as needed.

Evidence from a retrospective study suggests that, for most patients, early treatment of acute ITP does not appear to increase the risk for chronic ITP in the future, reported Chelsea L. Grama, a fourth-year medical student, and her colleagues from Penn State Health Children’s Hospital in Hershey, Pennsylvania.

“It’s controversial whether to treat or not. Some people think steroids are the best way to go, some think IVIG [intravenous immunoglobulin] is the best way to go, and some think that no treatment could be the best option. There is really no consensus in the literature to say what the ideal treatment for ITP is,” she commented in an interview at the annual meeting of the American Society of Pediatric Hematology/Oncology.

That lack of consensus is the result of the fact that serious consequences of ITP, such as intracranial hemorrhage, are rare, making it difficult for investigators to compare clinical outcomes with various forms of treatment. It’s also unclear whether early interventions could lead to later chronic disease.

In hopes of answering this question, Ms. Grama and her coinvestigators, led by Andrew S. Freiberg, MD, took a retrospective look at data on 249 patients with ITP diagnosed from birth through age 21 from 1994 to 2011.

They looked at demographic variables, treatments received, and subsequent platelet counts. Outcomes included intracranial hemorrhage and long-term improvements in platelet counts. They defined chronic ITP as a platelet count below 140,000/mcL for at least 6 months following diagnosis.

Of the 249 patients, 126 (66 boys and 60 girls) progressed to chronic ITP. The incidence of chronic ITP among treated patients was 51.1% and, in untreated patients, 49.3%.

However, in two subgroups, there was a significant association between treatment and chronic ITP. Among girls from birth through age 3 years, 58% of those treated went on to chronic ITP, compared with 0% for untreated patients (P = .008). When the age cohort was expanded to girls younger than 6 years, a similar pattern emerged, with chronic ITP rates of 45% for treated patients, compared with 0% for untreated patients. There were only 44 total patients in this age and sex subgroup, however, making it difficult to draw strong inferences about a potential relationship between treatment and chronic ITP, Ms. Grama noted.

Only three patients had cerebral hemorrhage. Two had hemorrhage as their initial ITP presentation, and the third had bleeding despite being on treatment. The sample size was too small to correlate the outcome with treatment, the authors noted.

In multivariate analysis controlling for demographic, clinical, and treatment factors, only age and platelet count at presentation independently predicted chronic thrombocytopenia (P less than .0001 for each). Steroid therapy was the only independent predictor for acute ITP (P = .0001).

Although their data suggest that there could be a benefit to treating patients who first present with acute ITP at age 12 years or older, “I do think it’s reasonable to wait and watch these patients,” Ms. Grama said.

“The incidence of brain bleeds, which is the really scary complication, was so low in these patients that I think watchful waiting would be a better way to go, just monitoring patients very closely. Hopefully, they will resolve without having treatment,” she added.

The study was internally supported. The authors reported no relevant disclosures.

MONTREAL – Clinicians who manage the care of children with newly diagnosed idiopathic thrombocytopenic purpura (ITP) have to decide whether to treat patients early and possibly increase risk for chronic ITP down the road or to leave well enough alone and treat only as needed.

Evidence from a retrospective study suggests that, for most patients, early treatment of acute ITP does not appear to increase the risk for chronic ITP in the future, reported Chelsea L. Grama, a fourth-year medical student, and her colleagues from Penn State Health Children’s Hospital in Hershey, Pennsylvania.

“It’s controversial whether to treat or not. Some people think steroids are the best way to go, some think IVIG [intravenous immunoglobulin] is the best way to go, and some think that no treatment could be the best option. There is really no consensus in the literature to say what the ideal treatment for ITP is,” she commented in an interview at the annual meeting of the American Society of Pediatric Hematology/Oncology.

That lack of consensus is the result of the fact that serious consequences of ITP, such as intracranial hemorrhage, are rare, making it difficult for investigators to compare clinical outcomes with various forms of treatment. It’s also unclear whether early interventions could lead to later chronic disease.

In hopes of answering this question, Ms. Grama and her coinvestigators, led by Andrew S. Freiberg, MD, took a retrospective look at data on 249 patients with ITP diagnosed from birth through age 21 from 1994 to 2011.

They looked at demographic variables, treatments received, and subsequent platelet counts. Outcomes included intracranial hemorrhage and long-term improvements in platelet counts. They defined chronic ITP as a platelet count below 140,000/mcL for at least 6 months following diagnosis.

Of the 249 patients, 126 (66 boys and 60 girls) progressed to chronic ITP. The incidence of chronic ITP among treated patients was 51.1% and, in untreated patients, 49.3%.

However, in two subgroups, there was a significant association between treatment and chronic ITP. Among girls from birth through age 3 years, 58% of those treated went on to chronic ITP, compared with 0% for untreated patients (P = .008). When the age cohort was expanded to girls younger than 6 years, a similar pattern emerged, with chronic ITP rates of 45% for treated patients, compared with 0% for untreated patients. There were only 44 total patients in this age and sex subgroup, however, making it difficult to draw strong inferences about a potential relationship between treatment and chronic ITP, Ms. Grama noted.

Only three patients had cerebral hemorrhage. Two had hemorrhage as their initial ITP presentation, and the third had bleeding despite being on treatment. The sample size was too small to correlate the outcome with treatment, the authors noted.

In multivariate analysis controlling for demographic, clinical, and treatment factors, only age and platelet count at presentation independently predicted chronic thrombocytopenia (P less than .0001 for each). Steroid therapy was the only independent predictor for acute ITP (P = .0001).

Although their data suggest that there could be a benefit to treating patients who first present with acute ITP at age 12 years or older, “I do think it’s reasonable to wait and watch these patients,” Ms. Grama said.

“The incidence of brain bleeds, which is the really scary complication, was so low in these patients that I think watchful waiting would be a better way to go, just monitoring patients very closely. Hopefully, they will resolve without having treatment,” she added.

The study was internally supported. The authors reported no relevant disclosures.

MONTREAL – Clinicians who manage the care of children with newly diagnosed idiopathic thrombocytopenic purpura (ITP) have to decide whether to treat patients early and possibly increase risk for chronic ITP down the road or to leave well enough alone and treat only as needed.

Evidence from a retrospective study suggests that, for most patients, early treatment of acute ITP does not appear to increase the risk for chronic ITP in the future, reported Chelsea L. Grama, a fourth-year medical student, and her colleagues from Penn State Health Children’s Hospital in Hershey, Pennsylvania.

“It’s controversial whether to treat or not. Some people think steroids are the best way to go, some think IVIG [intravenous immunoglobulin] is the best way to go, and some think that no treatment could be the best option. There is really no consensus in the literature to say what the ideal treatment for ITP is,” she commented in an interview at the annual meeting of the American Society of Pediatric Hematology/Oncology.

That lack of consensus is the result of the fact that serious consequences of ITP, such as intracranial hemorrhage, are rare, making it difficult for investigators to compare clinical outcomes with various forms of treatment. It’s also unclear whether early interventions could lead to later chronic disease.

In hopes of answering this question, Ms. Grama and her coinvestigators, led by Andrew S. Freiberg, MD, took a retrospective look at data on 249 patients with ITP diagnosed from birth through age 21 from 1994 to 2011.

They looked at demographic variables, treatments received, and subsequent platelet counts. Outcomes included intracranial hemorrhage and long-term improvements in platelet counts. They defined chronic ITP as a platelet count below 140,000/mcL for at least 6 months following diagnosis.

Of the 249 patients, 126 (66 boys and 60 girls) progressed to chronic ITP. The incidence of chronic ITP among treated patients was 51.1% and, in untreated patients, 49.3%.

However, in two subgroups, there was a significant association between treatment and chronic ITP. Among girls from birth through age 3 years, 58% of those treated went on to chronic ITP, compared with 0% for untreated patients (P = .008). When the age cohort was expanded to girls younger than 6 years, a similar pattern emerged, with chronic ITP rates of 45% for treated patients, compared with 0% for untreated patients. There were only 44 total patients in this age and sex subgroup, however, making it difficult to draw strong inferences about a potential relationship between treatment and chronic ITP, Ms. Grama noted.

Only three patients had cerebral hemorrhage. Two had hemorrhage as their initial ITP presentation, and the third had bleeding despite being on treatment. The sample size was too small to correlate the outcome with treatment, the authors noted.

In multivariate analysis controlling for demographic, clinical, and treatment factors, only age and platelet count at presentation independently predicted chronic thrombocytopenia (P less than .0001 for each). Steroid therapy was the only independent predictor for acute ITP (P = .0001).

Although their data suggest that there could be a benefit to treating patients who first present with acute ITP at age 12 years or older, “I do think it’s reasonable to wait and watch these patients,” Ms. Grama said.

“The incidence of brain bleeds, which is the really scary complication, was so low in these patients that I think watchful waiting would be a better way to go, just monitoring patients very closely. Hopefully, they will resolve without having treatment,” she added.

The study was internally supported. The authors reported no relevant disclosures.

LAS VEGAS – When the resident in the handoff training video approached another resident, she first vented about her “really crazy day” and how she’d been hoping to “get out of here on time for once.” Then, she tore through a case like an auctioneer, leaving out important details. At the end, she got a page and, of course, didn’t finish the handoff.

In Wednesday’s Quality Track session, “Strategies for Implementing a Successful Handoff” – with lessons from SHM’s I-PASS mentored implementation project – some attendees were eager to point out all of the flaws in the handoff. They were, however, slower to point to the good. For instance, the resident in the video made the effort to meet face-to-face and asked whether her colleague had any questions.

The audience had learned an important lesson about how to foster better handoffs, said Glenn Rosenbluth, MD, director of quality and safety programs at the University of California, San Francisco. He noted that it can be difficult to find the positives when the negatives are so glaring.

“This is one of the hard parts about doing feedback,” he said.

It was just one of many lessons taught in the session, also led by Amy Starmer, MD, MPH, a lecturer on pediatrics at Harvard Medical School, and Courtney Edgar-Zarate, MD, a pediatric hospitalist at Arkansas Children’s Hospital who was one of the I-PASS site leaders.

I-PASS was a nine-site study in the United States and Canada that found that using a bundle of interventions while doing handoffs resulted in a 30% reduction in preventable adverse events, meaning less harm to patients. The hallmark is the “I-PASS” mnemonic. It stands for:

• Illness severity – describing the stability level of a patient.
• Patient summary, including general information, such as the events leading to admission.
• Action list – essentially a to-do list for the patient.
• Situation awareness and contingency planning, which involves having a plan for what might happen.
• Synthesis by the receiver, in which the recipient of the information summarizes what was heard and asks questions.

Beyond that, the I-PASS system involves an introductory workshop, simulation exercises, structured observation and feedback, among other elements, Dr. Starmer said.

“This intervention was certainly not just a five-letter mnemonic,” she said.

The I-PASS Mentored Implementation Program, a collaboration with SHM that is funded by the Agency for Healthcare Research and Quality, is an effort to help implement a similar program in 32 hospitals in the United States.

Dr. Edgar-Zarate outlined the steps that worked at her site to make their I-PASS project successful. She said that project managers have to establish institutional support; assess a given center’s needs; gauge where to begin by identifying the most vulnerable transition points; find providers who will champion the project; establish good communication, in part by incorporating I-PASS into previously scheduled meetings; and collect data as time goes on.

Dr. Starmer directed attendees to www.ipassstudygroup.com, where anyone can download the material for free.

“This mentored implementation process,” she said, “has really been a helpful vehicle for disseminating the curriculum and implementation across different areas.”

LAS VEGAS – When the resident in the handoff training video approached another resident, she first vented about her “really crazy day” and how she’d been hoping to “get out of here on time for once.” Then, she tore through a case like an auctioneer, leaving out important details. At the end, she got a page and, of course, didn’t finish the handoff.

In Wednesday’s Quality Track session, “Strategies for Implementing a Successful Handoff” – with lessons from SHM’s I-PASS mentored implementation project – some attendees were eager to point out all of the flaws in the handoff. They were, however, slower to point to the good. For instance, the resident in the video made the effort to meet face-to-face and asked whether her colleague had any questions.

The audience had learned an important lesson about how to foster better handoffs, said Glenn Rosenbluth, MD, director of quality and safety programs at the University of California, San Francisco. He noted that it can be difficult to find the positives when the negatives are so glaring.

“This is one of the hard parts about doing feedback,” he said.

It was just one of many lessons taught in the session, also led by Amy Starmer, MD, MPH, a lecturer on pediatrics at Harvard Medical School, and Courtney Edgar-Zarate, MD, a pediatric hospitalist at Arkansas Children’s Hospital who was one of the I-PASS site leaders.

I-PASS was a nine-site study in the United States and Canada that found that using a bundle of interventions while doing handoffs resulted in a 30% reduction in preventable adverse events, meaning less harm to patients. The hallmark is the “I-PASS” mnemonic. It stands for:

• Illness severity – describing the stability level of a patient.
• Patient summary, including general information, such as the events leading to admission.
• Action list – essentially a to-do list for the patient.
• Situation awareness and contingency planning, which involves having a plan for what might happen.
• Synthesis by the receiver, in which the recipient of the information summarizes what was heard and asks questions.

Beyond that, the I-PASS system involves an introductory workshop, simulation exercises, structured observation and feedback, among other elements, Dr. Starmer said.

“This intervention was certainly not just a five-letter mnemonic,” she said.

The I-PASS Mentored Implementation Program, a collaboration with SHM that is funded by the Agency for Healthcare Research and Quality, is an effort to help implement a similar program in 32 hospitals in the United States.

Dr. Edgar-Zarate outlined the steps that worked at her site to make their I-PASS project successful. She said that project managers have to establish institutional support; assess a given center’s needs; gauge where to begin by identifying the most vulnerable transition points; find providers who will champion the project; establish good communication, in part by incorporating I-PASS into previously scheduled meetings; and collect data as time goes on.

Dr. Starmer directed attendees to www.ipassstudygroup.com, where anyone can download the material for free.

“This mentored implementation process,” she said, “has really been a helpful vehicle for disseminating the curriculum and implementation across different areas.”

LAS VEGAS – When the resident in the handoff training video approached another resident, she first vented about her “really crazy day” and how she’d been hoping to “get out of here on time for once.” Then, she tore through a case like an auctioneer, leaving out important details. At the end, she got a page and, of course, didn’t finish the handoff.

In Wednesday’s Quality Track session, “Strategies for Implementing a Successful Handoff” – with lessons from SHM’s I-PASS mentored implementation project – some attendees were eager to point out all of the flaws in the handoff. They were, however, slower to point to the good. For instance, the resident in the video made the effort to meet face-to-face and asked whether her colleague had any questions.

The audience had learned an important lesson about how to foster better handoffs, said Glenn Rosenbluth, MD, director of quality and safety programs at the University of California, San Francisco. He noted that it can be difficult to find the positives when the negatives are so glaring.

“This is one of the hard parts about doing feedback,” he said.

It was just one of many lessons taught in the session, also led by Amy Starmer, MD, MPH, a lecturer on pediatrics at Harvard Medical School, and Courtney Edgar-Zarate, MD, a pediatric hospitalist at Arkansas Children’s Hospital who was one of the I-PASS site leaders.

I-PASS was a nine-site study in the United States and Canada that found that using a bundle of interventions while doing handoffs resulted in a 30% reduction in preventable adverse events, meaning less harm to patients. The hallmark is the “I-PASS” mnemonic. It stands for:

• Illness severity – describing the stability level of a patient.
• Patient summary, including general information, such as the events leading to admission.
• Action list – essentially a to-do list for the patient.
• Situation awareness and contingency planning, which involves having a plan for what might happen.
• Synthesis by the receiver, in which the recipient of the information summarizes what was heard and asks questions.

Beyond that, the I-PASS system involves an introductory workshop, simulation exercises, structured observation and feedback, among other elements, Dr. Starmer said.

“This intervention was certainly not just a five-letter mnemonic,” she said.

The I-PASS Mentored Implementation Program, a collaboration with SHM that is funded by the Agency for Healthcare Research and Quality, is an effort to help implement a similar program in 32 hospitals in the United States.

Dr. Edgar-Zarate outlined the steps that worked at her site to make their I-PASS project successful. She said that project managers have to establish institutional support; assess a given center’s needs; gauge where to begin by identifying the most vulnerable transition points; find providers who will champion the project; establish good communication, in part by incorporating I-PASS into previously scheduled meetings; and collect data as time goes on.

Dr. Starmer directed attendees to www.ipassstudygroup.com, where anyone can download the material for free.

“This mentored implementation process,” she said, “has really been a helpful vehicle for disseminating the curriculum and implementation across different areas.”

Women should stop attending their cervical screening appointments at the recommended age of 65 and over only if they have an adequate prior screening history with negative results, researchers have warned.

“Messages about a ‘stopping age’ should emphasize the recommendation for an adequate screening history of previous negative tests before screening is discontinued, not just chronological age,” wrote the study authors. The report was published in the American Journal of Preventive Medicine (2017 May 1. doi: 10.1016/j.amepre.2017.02.024).

Leading professional organizations recommend “average-risk” women should be screened for cervical cancer between the ages of 21 and 65 years.

However, the authors, led by Mary C. White, ScD, of the Centers for Disease Control and Prevention, Atlanta, and her colleagues noted that data from 2013 showed that one-fifth of cervical cancer deaths occurred in women in the United States who were over the age of 65 years.

In the current study, the research team looked at data from the cross-sectional household National Health Interview Surveys from 2013 and 2015 to determine the number of women aged 41-70 years who had never had a Pap test or had not had one for 5 years or more.

After correcting for women who had undergone a hysterectomy, the researchers found that the incidence rate for cervical cancer increased with age until about 70 years and then declined after the age of 85.

Yet the proportion of women who had not been screened recently increased with age, from about 12% for women in their 40s to nearly 24% for women aged 66-70 years.

Efforts should be made to clarify misperceptions about the risk of cervical cancer among older women and health care providers, the investigators said.

“A recommended upper age limit for routine screening may lead women and providers to assume that cervical cancer is a younger woman’s disease,” they said.

Catch-up screening might be needed for underscreened women after the age of 65 years, although the physical and psychological issues associated with this should be taken into account, the study authors said.

“Age itself may need to be reconsidered, given high cervical cancer incidence rates after the age of 65 years, increases in life expectancy, and different human papillomavirus exposures by birth cohort,” they concluded.

Women should stop attending their cervical screening appointments at the recommended age of 65 and over only if they have an adequate prior screening history with negative results, researchers have warned.

“Messages about a ‘stopping age’ should emphasize the recommendation for an adequate screening history of previous negative tests before screening is discontinued, not just chronological age,” wrote the study authors. The report was published in the American Journal of Preventive Medicine (2017 May 1. doi: 10.1016/j.amepre.2017.02.024).

Leading professional organizations recommend “average-risk” women should be screened for cervical cancer between the ages of 21 and 65 years.

However, the authors, led by Mary C. White, ScD, of the Centers for Disease Control and Prevention, Atlanta, and her colleagues noted that data from 2013 showed that one-fifth of cervical cancer deaths occurred in women in the United States who were over the age of 65 years.

In the current study, the research team looked at data from the cross-sectional household National Health Interview Surveys from 2013 and 2015 to determine the number of women aged 41-70 years who had never had a Pap test or had not had one for 5 years or more.

After correcting for women who had undergone a hysterectomy, the researchers found that the incidence rate for cervical cancer increased with age until about 70 years and then declined after the age of 85.

Yet the proportion of women who had not been screened recently increased with age, from about 12% for women in their 40s to nearly 24% for women aged 66-70 years.

Efforts should be made to clarify misperceptions about the risk of cervical cancer among older women and health care providers, the investigators said.

“A recommended upper age limit for routine screening may lead women and providers to assume that cervical cancer is a younger woman’s disease,” they said.

Catch-up screening might be needed for underscreened women after the age of 65 years, although the physical and psychological issues associated with this should be taken into account, the study authors said.

“Age itself may need to be reconsidered, given high cervical cancer incidence rates after the age of 65 years, increases in life expectancy, and different human papillomavirus exposures by birth cohort,” they concluded.

Women should stop attending their cervical screening appointments at the recommended age of 65 and over only if they have an adequate prior screening history with negative results, researchers have warned.

“Messages about a ‘stopping age’ should emphasize the recommendation for an adequate screening history of previous negative tests before screening is discontinued, not just chronological age,” wrote the study authors. The report was published in the American Journal of Preventive Medicine (2017 May 1. doi: 10.1016/j.amepre.2017.02.024).

Leading professional organizations recommend “average-risk” women should be screened for cervical cancer between the ages of 21 and 65 years.

However, the authors, led by Mary C. White, ScD, of the Centers for Disease Control and Prevention, Atlanta, and her colleagues noted that data from 2013 showed that one-fifth of cervical cancer deaths occurred in women in the United States who were over the age of 65 years.

In the current study, the research team looked at data from the cross-sectional household National Health Interview Surveys from 2013 and 2015 to determine the number of women aged 41-70 years who had never had a Pap test or had not had one for 5 years or more.

After correcting for women who had undergone a hysterectomy, the researchers found that the incidence rate for cervical cancer increased with age until about 70 years and then declined after the age of 85.

Yet the proportion of women who had not been screened recently increased with age, from about 12% for women in their 40s to nearly 24% for women aged 66-70 years.

Efforts should be made to clarify misperceptions about the risk of cervical cancer among older women and health care providers, the investigators said.

“A recommended upper age limit for routine screening may lead women and providers to assume that cervical cancer is a younger woman’s disease,” they said.

Catch-up screening might be needed for underscreened women after the age of 65 years, although the physical and psychological issues associated with this should be taken into account, the study authors said.

“Age itself may need to be reconsidered, given high cervical cancer incidence rates after the age of 65 years, increases in life expectancy, and different human papillomavirus exposures by birth cohort,” they concluded.

Nonmelanoma skin cancer is the most common malignancy in the United States, with basal cell carcinoma (BCC) being the major histological subtype and accounting for approximately 80% of all skin cancers.^1-3 The age-adjusted incidence of BCC in the United States between 2004 and 2006 was estimated at 1019 cases per 100,000 in women and 1488 cases per 100,000 in men, and an estimated 2.8 million new cases are diagnosed in the United States each year.^3,4 Rates have been shown to increase with advancing age and are higher in males than females at all ages.³ Exposure to solar UVB radiation generally is considered to be the greatest risk factor for development of BCC.^3,5,6 Severe or frequent sunburn and recreational exposure to sun in childhood (from birth to 19 years of age), particularly in individuals who tend to burn rather than tan, have been shown to substantially increase the risk for developing BCC as an adult.⁷ Additional risk factors include light skin color, red or blonde hair color, presence of a large number of moles on the extremities, and a family history of melanoma or painful/blistering sunburn reactions.^3,7 Exposure to certain toxins, immunosuppression, and several genetic cancer syndromes also have been linked to BCC.⁵

Eighty percent of BCC cases involve the head and neck, with the trunk, arms, and legs being the next most common sites.⁵ Basal cell carcinoma can be classified by histologic subtype including nodular, superficial, nodulocystic, morpheic, metatypical, pigmented, and ulcerative, as well as other rarer forms.⁸ Elder⁹ recommended that it may be most clinically practical to divide BCC into subtypes that are known to have low (eg, nodular, nodulocystic) or relatively high risk for local recurrence (eg, infiltrating, morpheic, and metatypical).^9,10 The most common histologic subtype is nodular BCC, with an incidence of 40% to 60%, which typically presents as a red to white pearly nodule or papule with a rolled border; overlying telangiectasia; and occasionally crusting, ulceration, or a cyst.^5,11,12

Basal cell carcinoma generally is a slow-growing and highly curable form of skin cancer.^5,13,14 Compared to either squamous cell carcinoma or melanoma, BCC is generally easier to treat and carries a more favorable prognosis with a lower incidence of recurrence and metastasis.¹⁵ Malignancy in BCC is due to local growth and destruction of the primary tumor rather than metastasis, which is quite rare (estimated to occur in 0.0028% to 0.55% of cases) but carries a poor prognosis.^5,11,16 Basal cell carcinoma grows continuously along the path of least resistance, showing an affinity for the dermis, fascial planes, nerve sheaths, blood vessels, and lymphatic vessels. It is through these pathways that certain locally aggressive tumors can achieve great depths and distant spread. Tumors also are known to spread along embryonic fascial planes, which allows cells to extend in a direction perpendicular to the skin surface and achieve greater depths.¹³ Metastasis has been found to occur more frequently in white men, arising from large tumors larger than 7.5 cm on the head and neck with spread to local lymph nodes. The median survival rate in this group, even in patients receiving adjuvant chemotherapy or radiation, is 10 months but is lower in patients with larger tumors and those who neglect to seek medical care.¹⁶ Although mortality is low, its high and increasing prevalence makes BCC an important and costly health problem in the United States.^2,17

Case Report

A 60-year-old white man with a history of diabetes mellitus presented to the dermatology clinic with concerns about a nonhealing sore on the right upper back that had been present for more than 10 years and had gradually increased in size. The patient reported he did not have health insurance and thus did not seek medical care. Despite the size and location of the lesion, he was able to maintain an active lifestyle and worked as a janitor without difficulty until shortly before presentation when the lesion began to ooze and bleed, requiring him to change the dressing multiple times each day. The patient had no systemic symptoms and described himself as an otherwise healthy man.

On evaluation, the patient was noted to have a 20×15-cm ulcerated tumor on the right side of the upper back and shoulder with no satellite lesions (Figure 1). There were no palpable lymph nodes or satellite lesions and the rest of the physical examination was unremarkable. An 8-mm shave biopsy was collected on the day of presentation and sent for pathology to evaluate for suspected malignancy. On histology, BCC was present with islands of tumor cells extending from the epidermis into the dermis (Figure 2). These nests of cells displayed classic peripheral palisading of hyperchromatic, ovoid-shaped, basaloid nuclei at the periphery. Clefting around islands of tumor cells in the dermis also was apparent. Several foci suggested squamous differentiation, but the bulk of the lesion suggested a conventional nodular BCC.

The patient was referred to a surgical oncologist who recommended a wide surgical excision (SE) and delayed split-thickness skin graft (STSG) due to the size and location of the lesion. Eighteen days after receiving the diagnosis of BCC, the patient was taken to the operating room and underwent wide en bloc resection of the soft tissue tumor. Upon lifting the specimen off the underlying muscles, it was found to be penetrating into portions of the trapezius, deltoid, paraspinal, supraspinalis, and infraspinatus muscles. As such, the ulcerated tumor was removed as well as portions of the underlying musculature measuring 21×18 cm. The wound was left open until final pathology on margin clearance was available. It was covered with a wound vac to encourage granulation in anticipation of a planned delayed STSG. There were no complications, and the patient returned to the recovery unit in good condition where the dressing was replaced with a large wound vac system.

Final histologic examination showed negative deep and peripheral margins. More extensive examination of histology of the excised tumor was found to have characteristics consistent with metatypical and morpheic-type BCC. In addition to islands of tumor cells noted in the dermis on original biopsy, this sample also revealed basaloid cells arranged in thin elongated trabeculae invading deeper into the reticular dermis without peripheral palisading, suggestive of the morpheic variant (Figure 3A).^8,9,10 Other areas were found to have focal squamous differentiation with keratin pearls and intercellular bridges (Figure 3B). These findings support the diagnosis of a completely excised BCC of the metatypical (referred to by some authorities as basosquamous)^8,9 type.

The patient was seen for postoperative evaluations at 2 and 3 weeks. Each time granulation was noted to be proceeding well without signs of infection, and the wound vac was left in place. One month after the initial SE, the patient returned for the planned STSG. The skin graft was harvested from the right lateral thigh and was meshed and transferred to the recipient site on the right upper back, sewn circumferentially to the wound edges. Occlusive petrolatum gauze was placed over the graft followed by the wound vac for coverage until the graft matured.

The patient returned for follow-up approximately 7 months after his initial visit to the clinic. He reported feeling well, and his only concern was mild soreness of the scapular muscles while playing golf. The site of tumor excision showed 100% take of the STSG with no nodules in or around the site to suggest recurrence (Figure 4). The patient denied experiencing any constitutional symptoms and had no palpable lymph nodes or physical examination findings suggestive of metastatic disease or new tumor development at other sites. At 36 months after his initial clinic visit, he remained free of recurrence.

Comment

Typical BCC lesions are indolent and small, occurring primarily on the head and neck.^5,11,12,17 We report the case of a locally advanced, extremely large and penetrating lesion located on the trunk. This relatively unique case provides for an interesting comparison between available treatments for BCC as well as several of the generally accepted principles of management previously described in the literature.

Treatment Considerations

The approach to management of BCC considers factors related to the tumor and those related to the patient and practitioner. Telfer et al⁶ recommended that tumors be categorized as relatively low or high risk based on prognostic factors including size, site, histologic subtype and growth pattern; definition of margins; and presence or absence of prior treatment. Characteristics of high-risk tumors include size greater than 2.5 to 3 cm in diameter; location on the midface, nose, or ears; aggressive histologic subtype including morpheic, infiltrating, and metatypical; deep extension; perineural invasion; neglected or long-standing lesions; incomplete SE or Mohs micrographic surgery (MMS); and recurrence of tumor after prior treatment.^13,14,18 Although rare, tumors of the metatypical subtype are particularly important to identify, as they are known to be more aggressive and prone to spread than other forms of BCC.^19,20 The clinical appearance of metatypical BCCs often is identical to lower-risk subtypes, reinforcing the importance of careful histologic examination of an adequately deep biopsy, given that metatypical features often are present only in the deep tissue planes.¹⁹

The practitioner also must consider patient-related factors such as age, general health, immunocompromised states, coexisting medical conditions, and current medications. The skills, experience, and recommendations of the physician also are expected to influence treatment selection.^6,21

Surgical Versus Nonsurgical Treatment Approaches

Treatment of large, locally advanced, primary BCCs can be divided into surgical and nonsurgical approaches.^5,6 Surgical approaches include MMS and SE. Mohs micrographic surgery, electrodesiccation and curettage, and cryosurgery may achieve high cure rates in lesions that are low risk but generally are not recommended for use with recurrent or high-risk large and aggressive tumors.^5,6 Nonsurgical approaches include radiotherapy; chemotherapy; and vismodegib, an oral inhibitor of the hedgehog pathway involved in the development of many BCCs.^5,6,22 Topical photodynamic therapy with 5-aminolevulinic acid, topical imiquimod (immune-response modulator) and 5-fluorouracil, and intralesional interferon are other nonsurgical options that are primarily effective for small superficial BCCs. These modalities are not indicated for high-risk tumors.^5,6,23

For small tumors, MMS is regarded by most practitioners as the gold standard due to the high cure rate and cosmetic results it provides.^5,6,18,24 This procedure allows for precise mapping of tumor location on frozen sections and, unlike surgical excision, examination of close to 100% of the deep and peripheral margins.¹⁸ Excision and evaluation of thin horizontal sections for tumor extension also allows for a greater degree of tissue conservation than other modalities.^6,25 Mohs micrographic surgery is particularly useful for tumors of the midface, aggressive histologic subtype (eg, morpheic, infiltrating, basosquamous, micronodular), deep invasion, and perineural spread.^6,8,18,25 In a large review of 3 studies including a total of 7670 patients with primary BCC treated by MMS, Rowe et al²⁶ reported a 5-year recurrence rate of 1.0%, which was 8.7 times less than the weighted average of all non-MMS modalities. Similarly, in a large prospective review by Leibovitch et al,¹⁸ the 5-year recurrence rate of BCC treated with MMS was 1.4% in primary cases and 4.0% in previously recurrent cases.¹⁸ They reported that the main predictors of recurrence included longer tumor duration, more levels of excision required to obtain clear margins, notable subclinical extension, and prior recurrence. Interestingly, tumor and postexcision defect size did not predict recurrence.¹⁸ Margin-controlled excision with MMS was associated with higher success rates than modalities based on clinical margins without histologic control (eg, surgical excision, electrocautery, curettage) and potentially incomplete excision.^12,18

Although MMS has been demonstrated to have a high success rate, it has relative disadvantages. Tumors that are multicentric or have indistinct borders are more difficult to treat with MMS, and cure rates with MMS have been shown to decrease with increasing tumor diameter.^13,25 For example, reported cure rates are greater than 99% for MMS in BCCs less than 2 cm in diameter compared to 98.6% for those between 2 and 3 cm, and only 90.5% for those greater than 3 cm.²⁷ Mohs micrographic surgery requires a highly trained surgeon and can be extremely time consuming and labor intensive, particularly with large and locally aggressive tumors.^6,25 Tumors that involve fat and cartilage require modifications to standardized processing techniques, and deep wounds involving muscle and bone create technical challenges in maintaining orientation.²⁵ In the past, MMS was more expensive than other treatment modalities; however, cost analyses have demonstrated a near-equal cost of MMS compared to surgical excision with permanent section control and lower cost as compared to radiation therapy for selected cases.²⁸

Surgical excision also is considered a highly effective treatment of primary BCC and is the most commonly used treatment modality for BCC.^5,18,29 In this procedure, the peripheral and deep margins of excised tissue can be examined by a pathologist.⁶ Telfer et al⁶ recommended SE as the preferable treatment of choice for both large and small tumors in low-risk sites (ie, those that do not include the face) with nodular histology, tumors with morpheic histology in low-risk sites, and small (<2 cm) superficial tumors in high-risk sites. It is recommended that the size of surgical margins correlate with the likelihood of the presence of subclinical tumor extensions. Larger and morpheic-type BCCs require wider margins to achieve complete excision. In these cases, a 3-mm margin yields only a 66% cure rate, while 5-mm margins yield an 82% cure rate and 13- to 15-mm margins yield cure rates higher than 95%.^6,29,30 In a series examining recurrence rates of primary BCC, Rowe et al²⁶ reviewed 10 studies (2606 patients treated by SE) and calculated a 5-year recurrence rate of 10.1%. Silverman et al³¹ reviewed 5-year recurrence rates in 588 cases of BCC treated with SE. They concluded that BCC on the neck, trunk, arms, and legs of any size may be effectively treated with this modality, with 1 case of recurrence among 187 cases (0.5% recurrence rate). Multivariate analysis identified 2 independent risk factors for recurrence: anatomic site (head) and patient sex (male). Analysis of BCCs on the head distinct from other body sites demonstrated a moderately significant trend (P=.196) of increasing diameter with increasing recurrence rates. Age at treatment, duration of lesion, and length of treatment were not significantly associated with an increased risk of recurrence.³¹ Similarly, a review of 1417 cases of BCC by Dubin and Kopf²¹ demonstrated an increased risk with tumors located on the head and larger lesions.

RELATED ARTICLE: Basal Cell Carcinoma: Analysis of Factors Associated With Incomplete Excision

Radiotherapy (RT) is a commonly employed nonsurgical approach to management. Its use has been declining in recent years due to relative disadvantages and side effects. Similar to MMS, it can be extremely effective for carefully selected patients.^11,31 Radiotherapy is most effective for use with aggressive, rapidly growing BCC subtypes that are more sensitive to radiation, as replicating cells undergo mitotic death when radiation is applied.¹⁵ Radiotherapy is considered a viable option for patients who are not candidates for surgery, tumors in locations difficult to access for SE, and for rare unresectable tumors as a primary therapy.^5,11 In a randomized comparison between RT and SE approaches to the treatment of primary BCCs on the face, RT was found to be inferior to SE both in efficacy (4-year recurrence rate, 7.5% vs 0.7%) and cosmesis (rate of good results, 69% vs 87%).³²

The major disadvantages of RT as compared to other treatment modalities such as MMS or SE are the lack of control at margins and compromised inferior cosmetic outcomes. Hair loss, hyperpigmentation or hypopigmentation, telangiectasia, keloids, cutaneous necrosis, and RT-induced dermatitis have been reported as side effects of RT.^6,11,32-34 Other disadvantages of RT include the inconvenience of multiple visits to the hospital for treatment, and high cost as compared to other modalities such as MMS.³⁵ Finally, use of RT even for relatively benign disease has been linked to an increased risk for both squamous cell carcinoma, BCC, and sarcomas.^15,36

Vismodegib is an oral drug approved by the US Food and Drug Administration in 2012 for the treatment of locally advanced BCC. It is a first-in-class small-molecule systemic inhibitor of the intracellular hedgehog signaling pathway, which has been implicated in the growth and development of several types of cancer, including BCC.^36-38 Most patients with BCC carry loss-of-function mutations that affect PTCH1 and result in unregulated reactivation of the hedgehog pathway and uncontrolled cell growth.^38-40 Vismodegib is a small molecule that selectively deactivates the hedgehog pathway. It currently is indicated for the treatment of metastatic BCC or patients with locally advanced BCCs who are not candidates for SE or RT.^38-41 An open-label nonrandomized phase 2 study by Sekulic et al⁴² evaluated the effectiveness of vismodegib for treatment of metastatic or inoperable BCCs. In 33 patients with metastatic BCCs, the response rate was 30% (10/33) with a 9.5-month median progression-free survival. All responses were partial, with 73% (24/33) showing tumor shrinkage. In 63 patients with locally advanced BCCs, the response rate was 43% (27/63). Most patients demonstrated visible reductions in tumor size and improvement in appearance, but 13 patients (21%) in this group were noted to have a complete response (ie, absence of residual BCC on biopsy). Both cohorts had a median response time of 7.6 months.⁴²

Conclusion

Our patient presented with an extremely large and ulcerating lesion on the upper back that met the criteria for classification as a high-risk tumor. In light of the tumor location and size as well as the involvement of deep tissues and muscles, we elected to pursue SE for management. This modality proved to be extremely effective, and the patient continues to be free of residual or recurrent BCC more than 36 months after surgery. Two large systematic reviews lend support to this management approach and report excellent outcomes. In a review article by Rubin et al,⁵ SE was shown to provide cure rates greater than 99% for BCC lesions of any size on the neck, trunk, and extremities. Moreover, Thissen et al⁴³ performed a systematic meta-analysis of 18 studies reporting recurrence rates of primary BCC after treatment with various modalities and concluded that when surgery is not contraindicated, SE is the treatment of choice for nodular and superficial BCC. Both groups agree in their recommendations that MMS should be used for BCCs in cosmetically compromised zones (eg, midface), sites where tissue sparing is essential, aggressive growth patterns (eg, perineural invasion, morpheaform histology), and when high risk of recurrence is unacceptable.^5,43 In contrast, MMS is not recommended for tumors of large diameter or with indistinct borders due to decreased cure rates.^13,25,27 Vismodegib is an interesting new option in development for management of metastatic and aggressive nonresectable BCCs. It was not an option in our patient. Although consideration for use of vismodegib as a neoadjuvant treatment to shrink the tumor prior to surgery is reasonable, the decision to proceed directly with SE proved to be the superior option for our patient.

Nonmelanoma skin cancer is the most common malignancy in the United States, with basal cell carcinoma (BCC) being the major histological subtype and accounting for approximately 80% of all skin cancers.^1-3 The age-adjusted incidence of BCC in the United States between 2004 and 2006 was estimated at 1019 cases per 100,000 in women and 1488 cases per 100,000 in men, and an estimated 2.8 million new cases are diagnosed in the United States each year.^3,4 Rates have been shown to increase with advancing age and are higher in males than females at all ages.³ Exposure to solar UVB radiation generally is considered to be the greatest risk factor for development of BCC.^3,5,6 Severe or frequent sunburn and recreational exposure to sun in childhood (from birth to 19 years of age), particularly in individuals who tend to burn rather than tan, have been shown to substantially increase the risk for developing BCC as an adult.⁷ Additional risk factors include light skin color, red or blonde hair color, presence of a large number of moles on the extremities, and a family history of melanoma or painful/blistering sunburn reactions.^3,7 Exposure to certain toxins, immunosuppression, and several genetic cancer syndromes also have been linked to BCC.⁵

Eighty percent of BCC cases involve the head and neck, with the trunk, arms, and legs being the next most common sites.⁵ Basal cell carcinoma can be classified by histologic subtype including nodular, superficial, nodulocystic, morpheic, metatypical, pigmented, and ulcerative, as well as other rarer forms.⁸ Elder⁹ recommended that it may be most clinically practical to divide BCC into subtypes that are known to have low (eg, nodular, nodulocystic) or relatively high risk for local recurrence (eg, infiltrating, morpheic, and metatypical).^9,10 The most common histologic subtype is nodular BCC, with an incidence of 40% to 60%, which typically presents as a red to white pearly nodule or papule with a rolled border; overlying telangiectasia; and occasionally crusting, ulceration, or a cyst.^5,11,12

Basal cell carcinoma generally is a slow-growing and highly curable form of skin cancer.^5,13,14 Compared to either squamous cell carcinoma or melanoma, BCC is generally easier to treat and carries a more favorable prognosis with a lower incidence of recurrence and metastasis.¹⁵ Malignancy in BCC is due to local growth and destruction of the primary tumor rather than metastasis, which is quite rare (estimated to occur in 0.0028% to 0.55% of cases) but carries a poor prognosis.^5,11,16 Basal cell carcinoma grows continuously along the path of least resistance, showing an affinity for the dermis, fascial planes, nerve sheaths, blood vessels, and lymphatic vessels. It is through these pathways that certain locally aggressive tumors can achieve great depths and distant spread. Tumors also are known to spread along embryonic fascial planes, which allows cells to extend in a direction perpendicular to the skin surface and achieve greater depths.¹³ Metastasis has been found to occur more frequently in white men, arising from large tumors larger than 7.5 cm on the head and neck with spread to local lymph nodes. The median survival rate in this group, even in patients receiving adjuvant chemotherapy or radiation, is 10 months but is lower in patients with larger tumors and those who neglect to seek medical care.¹⁶ Although mortality is low, its high and increasing prevalence makes BCC an important and costly health problem in the United States.^2,17

Case Report

A 60-year-old white man with a history of diabetes mellitus presented to the dermatology clinic with concerns about a nonhealing sore on the right upper back that had been present for more than 10 years and had gradually increased in size. The patient reported he did not have health insurance and thus did not seek medical care. Despite the size and location of the lesion, he was able to maintain an active lifestyle and worked as a janitor without difficulty until shortly before presentation when the lesion began to ooze and bleed, requiring him to change the dressing multiple times each day. The patient had no systemic symptoms and described himself as an otherwise healthy man.

On evaluation, the patient was noted to have a 20×15-cm ulcerated tumor on the right side of the upper back and shoulder with no satellite lesions (Figure 1). There were no palpable lymph nodes or satellite lesions and the rest of the physical examination was unremarkable. An 8-mm shave biopsy was collected on the day of presentation and sent for pathology to evaluate for suspected malignancy. On histology, BCC was present with islands of tumor cells extending from the epidermis into the dermis (Figure 2). These nests of cells displayed classic peripheral palisading of hyperchromatic, ovoid-shaped, basaloid nuclei at the periphery. Clefting around islands of tumor cells in the dermis also was apparent. Several foci suggested squamous differentiation, but the bulk of the lesion suggested a conventional nodular BCC.

The patient was referred to a surgical oncologist who recommended a wide surgical excision (SE) and delayed split-thickness skin graft (STSG) due to the size and location of the lesion. Eighteen days after receiving the diagnosis of BCC, the patient was taken to the operating room and underwent wide en bloc resection of the soft tissue tumor. Upon lifting the specimen off the underlying muscles, it was found to be penetrating into portions of the trapezius, deltoid, paraspinal, supraspinalis, and infraspinatus muscles. As such, the ulcerated tumor was removed as well as portions of the underlying musculature measuring 21×18 cm. The wound was left open until final pathology on margin clearance was available. It was covered with a wound vac to encourage granulation in anticipation of a planned delayed STSG. There were no complications, and the patient returned to the recovery unit in good condition where the dressing was replaced with a large wound vac system.

Final histologic examination showed negative deep and peripheral margins. More extensive examination of histology of the excised tumor was found to have characteristics consistent with metatypical and morpheic-type BCC. In addition to islands of tumor cells noted in the dermis on original biopsy, this sample also revealed basaloid cells arranged in thin elongated trabeculae invading deeper into the reticular dermis without peripheral palisading, suggestive of the morpheic variant (Figure 3A).^8,9,10 Other areas were found to have focal squamous differentiation with keratin pearls and intercellular bridges (Figure 3B). These findings support the diagnosis of a completely excised BCC of the metatypical (referred to by some authorities as basosquamous)^8,9 type.

The patient was seen for postoperative evaluations at 2 and 3 weeks. Each time granulation was noted to be proceeding well without signs of infection, and the wound vac was left in place. One month after the initial SE, the patient returned for the planned STSG. The skin graft was harvested from the right lateral thigh and was meshed and transferred to the recipient site on the right upper back, sewn circumferentially to the wound edges. Occlusive petrolatum gauze was placed over the graft followed by the wound vac for coverage until the graft matured.

The patient returned for follow-up approximately 7 months after his initial visit to the clinic. He reported feeling well, and his only concern was mild soreness of the scapular muscles while playing golf. The site of tumor excision showed 100% take of the STSG with no nodules in or around the site to suggest recurrence (Figure 4). The patient denied experiencing any constitutional symptoms and had no palpable lymph nodes or physical examination findings suggestive of metastatic disease or new tumor development at other sites. At 36 months after his initial clinic visit, he remained free of recurrence.

Comment

Typical BCC lesions are indolent and small, occurring primarily on the head and neck.^5,11,12,17 We report the case of a locally advanced, extremely large and penetrating lesion located on the trunk. This relatively unique case provides for an interesting comparison between available treatments for BCC as well as several of the generally accepted principles of management previously described in the literature.

Treatment Considerations

The approach to management of BCC considers factors related to the tumor and those related to the patient and practitioner. Telfer et al⁶ recommended that tumors be categorized as relatively low or high risk based on prognostic factors including size, site, histologic subtype and growth pattern; definition of margins; and presence or absence of prior treatment. Characteristics of high-risk tumors include size greater than 2.5 to 3 cm in diameter; location on the midface, nose, or ears; aggressive histologic subtype including morpheic, infiltrating, and metatypical; deep extension; perineural invasion; neglected or long-standing lesions; incomplete SE or Mohs micrographic surgery (MMS); and recurrence of tumor after prior treatment.^13,14,18 Although rare, tumors of the metatypical subtype are particularly important to identify, as they are known to be more aggressive and prone to spread than other forms of BCC.^19,20 The clinical appearance of metatypical BCCs often is identical to lower-risk subtypes, reinforcing the importance of careful histologic examination of an adequately deep biopsy, given that metatypical features often are present only in the deep tissue planes.¹⁹

The practitioner also must consider patient-related factors such as age, general health, immunocompromised states, coexisting medical conditions, and current medications. The skills, experience, and recommendations of the physician also are expected to influence treatment selection.^6,21

Surgical Versus Nonsurgical Treatment Approaches

Treatment of large, locally advanced, primary BCCs can be divided into surgical and nonsurgical approaches.^5,6 Surgical approaches include MMS and SE. Mohs micrographic surgery, electrodesiccation and curettage, and cryosurgery may achieve high cure rates in lesions that are low risk but generally are not recommended for use with recurrent or high-risk large and aggressive tumors.^5,6 Nonsurgical approaches include radiotherapy; chemotherapy; and vismodegib, an oral inhibitor of the hedgehog pathway involved in the development of many BCCs.^5,6,22 Topical photodynamic therapy with 5-aminolevulinic acid, topical imiquimod (immune-response modulator) and 5-fluorouracil, and intralesional interferon are other nonsurgical options that are primarily effective for small superficial BCCs. These modalities are not indicated for high-risk tumors.^5,6,23

For small tumors, MMS is regarded by most practitioners as the gold standard due to the high cure rate and cosmetic results it provides.^5,6,18,24 This procedure allows for precise mapping of tumor location on frozen sections and, unlike surgical excision, examination of close to 100% of the deep and peripheral margins.¹⁸ Excision and evaluation of thin horizontal sections for tumor extension also allows for a greater degree of tissue conservation than other modalities.^6,25 Mohs micrographic surgery is particularly useful for tumors of the midface, aggressive histologic subtype (eg, morpheic, infiltrating, basosquamous, micronodular), deep invasion, and perineural spread.^6,8,18,25 In a large review of 3 studies including a total of 7670 patients with primary BCC treated by MMS, Rowe et al²⁶ reported a 5-year recurrence rate of 1.0%, which was 8.7 times less than the weighted average of all non-MMS modalities. Similarly, in a large prospective review by Leibovitch et al,¹⁸ the 5-year recurrence rate of BCC treated with MMS was 1.4% in primary cases and 4.0% in previously recurrent cases.¹⁸ They reported that the main predictors of recurrence included longer tumor duration, more levels of excision required to obtain clear margins, notable subclinical extension, and prior recurrence. Interestingly, tumor and postexcision defect size did not predict recurrence.¹⁸ Margin-controlled excision with MMS was associated with higher success rates than modalities based on clinical margins without histologic control (eg, surgical excision, electrocautery, curettage) and potentially incomplete excision.^12,18

Although MMS has been demonstrated to have a high success rate, it has relative disadvantages. Tumors that are multicentric or have indistinct borders are more difficult to treat with MMS, and cure rates with MMS have been shown to decrease with increasing tumor diameter.^13,25 For example, reported cure rates are greater than 99% for MMS in BCCs less than 2 cm in diameter compared to 98.6% for those between 2 and 3 cm, and only 90.5% for those greater than 3 cm.²⁷ Mohs micrographic surgery requires a highly trained surgeon and can be extremely time consuming and labor intensive, particularly with large and locally aggressive tumors.^6,25 Tumors that involve fat and cartilage require modifications to standardized processing techniques, and deep wounds involving muscle and bone create technical challenges in maintaining orientation.²⁵ In the past, MMS was more expensive than other treatment modalities; however, cost analyses have demonstrated a near-equal cost of MMS compared to surgical excision with permanent section control and lower cost as compared to radiation therapy for selected cases.²⁸

Surgical excision also is considered a highly effective treatment of primary BCC and is the most commonly used treatment modality for BCC.^5,18,29 In this procedure, the peripheral and deep margins of excised tissue can be examined by a pathologist.⁶ Telfer et al⁶ recommended SE as the preferable treatment of choice for both large and small tumors in low-risk sites (ie, those that do not include the face) with nodular histology, tumors with morpheic histology in low-risk sites, and small (<2 cm) superficial tumors in high-risk sites. It is recommended that the size of surgical margins correlate with the likelihood of the presence of subclinical tumor extensions. Larger and morpheic-type BCCs require wider margins to achieve complete excision. In these cases, a 3-mm margin yields only a 66% cure rate, while 5-mm margins yield an 82% cure rate and 13- to 15-mm margins yield cure rates higher than 95%.^6,29,30 In a series examining recurrence rates of primary BCC, Rowe et al²⁶ reviewed 10 studies (2606 patients treated by SE) and calculated a 5-year recurrence rate of 10.1%. Silverman et al³¹ reviewed 5-year recurrence rates in 588 cases of BCC treated with SE. They concluded that BCC on the neck, trunk, arms, and legs of any size may be effectively treated with this modality, with 1 case of recurrence among 187 cases (0.5% recurrence rate). Multivariate analysis identified 2 independent risk factors for recurrence: anatomic site (head) and patient sex (male). Analysis of BCCs on the head distinct from other body sites demonstrated a moderately significant trend (P=.196) of increasing diameter with increasing recurrence rates. Age at treatment, duration of lesion, and length of treatment were not significantly associated with an increased risk of recurrence.³¹ Similarly, a review of 1417 cases of BCC by Dubin and Kopf²¹ demonstrated an increased risk with tumors located on the head and larger lesions.

RELATED ARTICLE: Basal Cell Carcinoma: Analysis of Factors Associated With Incomplete Excision

Radiotherapy (RT) is a commonly employed nonsurgical approach to management. Its use has been declining in recent years due to relative disadvantages and side effects. Similar to MMS, it can be extremely effective for carefully selected patients.^11,31 Radiotherapy is most effective for use with aggressive, rapidly growing BCC subtypes that are more sensitive to radiation, as replicating cells undergo mitotic death when radiation is applied.¹⁵ Radiotherapy is considered a viable option for patients who are not candidates for surgery, tumors in locations difficult to access for SE, and for rare unresectable tumors as a primary therapy.^5,11 In a randomized comparison between RT and SE approaches to the treatment of primary BCCs on the face, RT was found to be inferior to SE both in efficacy (4-year recurrence rate, 7.5% vs 0.7%) and cosmesis (rate of good results, 69% vs 87%).³²

The major disadvantages of RT as compared to other treatment modalities such as MMS or SE are the lack of control at margins and compromised inferior cosmetic outcomes. Hair loss, hyperpigmentation or hypopigmentation, telangiectasia, keloids, cutaneous necrosis, and RT-induced dermatitis have been reported as side effects of RT.^6,11,32-34 Other disadvantages of RT include the inconvenience of multiple visits to the hospital for treatment, and high cost as compared to other modalities such as MMS.³⁵ Finally, use of RT even for relatively benign disease has been linked to an increased risk for both squamous cell carcinoma, BCC, and sarcomas.^15,36

Vismodegib is an oral drug approved by the US Food and Drug Administration in 2012 for the treatment of locally advanced BCC. It is a first-in-class small-molecule systemic inhibitor of the intracellular hedgehog signaling pathway, which has been implicated in the growth and development of several types of cancer, including BCC.^36-38 Most patients with BCC carry loss-of-function mutations that affect PTCH1 and result in unregulated reactivation of the hedgehog pathway and uncontrolled cell growth.^38-40 Vismodegib is a small molecule that selectively deactivates the hedgehog pathway. It currently is indicated for the treatment of metastatic BCC or patients with locally advanced BCCs who are not candidates for SE or RT.^38-41 An open-label nonrandomized phase 2 study by Sekulic et al⁴² evaluated the effectiveness of vismodegib for treatment of metastatic or inoperable BCCs. In 33 patients with metastatic BCCs, the response rate was 30% (10/33) with a 9.5-month median progression-free survival. All responses were partial, with 73% (24/33) showing tumor shrinkage. In 63 patients with locally advanced BCCs, the response rate was 43% (27/63). Most patients demonstrated visible reductions in tumor size and improvement in appearance, but 13 patients (21%) in this group were noted to have a complete response (ie, absence of residual BCC on biopsy). Both cohorts had a median response time of 7.6 months.⁴²

Conclusion

Our patient presented with an extremely large and ulcerating lesion on the upper back that met the criteria for classification as a high-risk tumor. In light of the tumor location and size as well as the involvement of deep tissues and muscles, we elected to pursue SE for management. This modality proved to be extremely effective, and the patient continues to be free of residual or recurrent BCC more than 36 months after surgery. Two large systematic reviews lend support to this management approach and report excellent outcomes. In a review article by Rubin et al,⁵ SE was shown to provide cure rates greater than 99% for BCC lesions of any size on the neck, trunk, and extremities. Moreover, Thissen et al⁴³ performed a systematic meta-analysis of 18 studies reporting recurrence rates of primary BCC after treatment with various modalities and concluded that when surgery is not contraindicated, SE is the treatment of choice for nodular and superficial BCC. Both groups agree in their recommendations that MMS should be used for BCCs in cosmetically compromised zones (eg, midface), sites where tissue sparing is essential, aggressive growth patterns (eg, perineural invasion, morpheaform histology), and when high risk of recurrence is unacceptable.^5,43 In contrast, MMS is not recommended for tumors of large diameter or with indistinct borders due to decreased cure rates.^13,25,27 Vismodegib is an interesting new option in development for management of metastatic and aggressive nonresectable BCCs. It was not an option in our patient. Although consideration for use of vismodegib as a neoadjuvant treatment to shrink the tumor prior to surgery is reasonable, the decision to proceed directly with SE proved to be the superior option for our patient.

Nonmelanoma skin cancer is the most common malignancy in the United States, with basal cell carcinoma (BCC) being the major histological subtype and accounting for approximately 80% of all skin cancers.^1-3 The age-adjusted incidence of BCC in the United States between 2004 and 2006 was estimated at 1019 cases per 100,000 in women and 1488 cases per 100,000 in men, and an estimated 2.8 million new cases are diagnosed in the United States each year.^3,4 Rates have been shown to increase with advancing age and are higher in males than females at all ages.³ Exposure to solar UVB radiation generally is considered to be the greatest risk factor for development of BCC.^3,5,6 Severe or frequent sunburn and recreational exposure to sun in childhood (from birth to 19 years of age), particularly in individuals who tend to burn rather than tan, have been shown to substantially increase the risk for developing BCC as an adult.⁷ Additional risk factors include light skin color, red or blonde hair color, presence of a large number of moles on the extremities, and a family history of melanoma or painful/blistering sunburn reactions.^3,7 Exposure to certain toxins, immunosuppression, and several genetic cancer syndromes also have been linked to BCC.⁵

Eighty percent of BCC cases involve the head and neck, with the trunk, arms, and legs being the next most common sites.⁵ Basal cell carcinoma can be classified by histologic subtype including nodular, superficial, nodulocystic, morpheic, metatypical, pigmented, and ulcerative, as well as other rarer forms.⁸ Elder⁹ recommended that it may be most clinically practical to divide BCC into subtypes that are known to have low (eg, nodular, nodulocystic) or relatively high risk for local recurrence (eg, infiltrating, morpheic, and metatypical).^9,10 The most common histologic subtype is nodular BCC, with an incidence of 40% to 60%, which typically presents as a red to white pearly nodule or papule with a rolled border; overlying telangiectasia; and occasionally crusting, ulceration, or a cyst.^5,11,12

Basal cell carcinoma generally is a slow-growing and highly curable form of skin cancer.^5,13,14 Compared to either squamous cell carcinoma or melanoma, BCC is generally easier to treat and carries a more favorable prognosis with a lower incidence of recurrence and metastasis.¹⁵ Malignancy in BCC is due to local growth and destruction of the primary tumor rather than metastasis, which is quite rare (estimated to occur in 0.0028% to 0.55% of cases) but carries a poor prognosis.^5,11,16 Basal cell carcinoma grows continuously along the path of least resistance, showing an affinity for the dermis, fascial planes, nerve sheaths, blood vessels, and lymphatic vessels. It is through these pathways that certain locally aggressive tumors can achieve great depths and distant spread. Tumors also are known to spread along embryonic fascial planes, which allows cells to extend in a direction perpendicular to the skin surface and achieve greater depths.¹³ Metastasis has been found to occur more frequently in white men, arising from large tumors larger than 7.5 cm on the head and neck with spread to local lymph nodes. The median survival rate in this group, even in patients receiving adjuvant chemotherapy or radiation, is 10 months but is lower in patients with larger tumors and those who neglect to seek medical care.¹⁶ Although mortality is low, its high and increasing prevalence makes BCC an important and costly health problem in the United States.^2,17

Case Report

A 60-year-old white man with a history of diabetes mellitus presented to the dermatology clinic with concerns about a nonhealing sore on the right upper back that had been present for more than 10 years and had gradually increased in size. The patient reported he did not have health insurance and thus did not seek medical care. Despite the size and location of the lesion, he was able to maintain an active lifestyle and worked as a janitor without difficulty until shortly before presentation when the lesion began to ooze and bleed, requiring him to change the dressing multiple times each day. The patient had no systemic symptoms and described himself as an otherwise healthy man.

On evaluation, the patient was noted to have a 20×15-cm ulcerated tumor on the right side of the upper back and shoulder with no satellite lesions (Figure 1). There were no palpable lymph nodes or satellite lesions and the rest of the physical examination was unremarkable. An 8-mm shave biopsy was collected on the day of presentation and sent for pathology to evaluate for suspected malignancy. On histology, BCC was present with islands of tumor cells extending from the epidermis into the dermis (Figure 2). These nests of cells displayed classic peripheral palisading of hyperchromatic, ovoid-shaped, basaloid nuclei at the periphery. Clefting around islands of tumor cells in the dermis also was apparent. Several foci suggested squamous differentiation, but the bulk of the lesion suggested a conventional nodular BCC.

The patient was referred to a surgical oncologist who recommended a wide surgical excision (SE) and delayed split-thickness skin graft (STSG) due to the size and location of the lesion. Eighteen days after receiving the diagnosis of BCC, the patient was taken to the operating room and underwent wide en bloc resection of the soft tissue tumor. Upon lifting the specimen off the underlying muscles, it was found to be penetrating into portions of the trapezius, deltoid, paraspinal, supraspinalis, and infraspinatus muscles. As such, the ulcerated tumor was removed as well as portions of the underlying musculature measuring 21×18 cm. The wound was left open until final pathology on margin clearance was available. It was covered with a wound vac to encourage granulation in anticipation of a planned delayed STSG. There were no complications, and the patient returned to the recovery unit in good condition where the dressing was replaced with a large wound vac system.

Final histologic examination showed negative deep and peripheral margins. More extensive examination of histology of the excised tumor was found to have characteristics consistent with metatypical and morpheic-type BCC. In addition to islands of tumor cells noted in the dermis on original biopsy, this sample also revealed basaloid cells arranged in thin elongated trabeculae invading deeper into the reticular dermis without peripheral palisading, suggestive of the morpheic variant (Figure 3A).^8,9,10 Other areas were found to have focal squamous differentiation with keratin pearls and intercellular bridges (Figure 3B). These findings support the diagnosis of a completely excised BCC of the metatypical (referred to by some authorities as basosquamous)^8,9 type.

The patient was seen for postoperative evaluations at 2 and 3 weeks. Each time granulation was noted to be proceeding well without signs of infection, and the wound vac was left in place. One month after the initial SE, the patient returned for the planned STSG. The skin graft was harvested from the right lateral thigh and was meshed and transferred to the recipient site on the right upper back, sewn circumferentially to the wound edges. Occlusive petrolatum gauze was placed over the graft followed by the wound vac for coverage until the graft matured.

The patient returned for follow-up approximately 7 months after his initial visit to the clinic. He reported feeling well, and his only concern was mild soreness of the scapular muscles while playing golf. The site of tumor excision showed 100% take of the STSG with no nodules in or around the site to suggest recurrence (Figure 4). The patient denied experiencing any constitutional symptoms and had no palpable lymph nodes or physical examination findings suggestive of metastatic disease or new tumor development at other sites. At 36 months after his initial clinic visit, he remained free of recurrence.

Comment

Typical BCC lesions are indolent and small, occurring primarily on the head and neck.^5,11,12,17 We report the case of a locally advanced, extremely large and penetrating lesion located on the trunk. This relatively unique case provides for an interesting comparison between available treatments for BCC as well as several of the generally accepted principles of management previously described in the literature.

Treatment Considerations

The approach to management of BCC considers factors related to the tumor and those related to the patient and practitioner. Telfer et al⁶ recommended that tumors be categorized as relatively low or high risk based on prognostic factors including size, site, histologic subtype and growth pattern; definition of margins; and presence or absence of prior treatment. Characteristics of high-risk tumors include size greater than 2.5 to 3 cm in diameter; location on the midface, nose, or ears; aggressive histologic subtype including morpheic, infiltrating, and metatypical; deep extension; perineural invasion; neglected or long-standing lesions; incomplete SE or Mohs micrographic surgery (MMS); and recurrence of tumor after prior treatment.^13,14,18 Although rare, tumors of the metatypical subtype are particularly important to identify, as they are known to be more aggressive and prone to spread than other forms of BCC.^19,20 The clinical appearance of metatypical BCCs often is identical to lower-risk subtypes, reinforcing the importance of careful histologic examination of an adequately deep biopsy, given that metatypical features often are present only in the deep tissue planes.¹⁹

The practitioner also must consider patient-related factors such as age, general health, immunocompromised states, coexisting medical conditions, and current medications. The skills, experience, and recommendations of the physician also are expected to influence treatment selection.^6,21

Surgical Versus Nonsurgical Treatment Approaches

Treatment of large, locally advanced, primary BCCs can be divided into surgical and nonsurgical approaches.^5,6 Surgical approaches include MMS and SE. Mohs micrographic surgery, electrodesiccation and curettage, and cryosurgery may achieve high cure rates in lesions that are low risk but generally are not recommended for use with recurrent or high-risk large and aggressive tumors.^5,6 Nonsurgical approaches include radiotherapy; chemotherapy; and vismodegib, an oral inhibitor of the hedgehog pathway involved in the development of many BCCs.^5,6,22 Topical photodynamic therapy with 5-aminolevulinic acid, topical imiquimod (immune-response modulator) and 5-fluorouracil, and intralesional interferon are other nonsurgical options that are primarily effective for small superficial BCCs. These modalities are not indicated for high-risk tumors.^5,6,23

For small tumors, MMS is regarded by most practitioners as the gold standard due to the high cure rate and cosmetic results it provides.^5,6,18,24 This procedure allows for precise mapping of tumor location on frozen sections and, unlike surgical excision, examination of close to 100% of the deep and peripheral margins.¹⁸ Excision and evaluation of thin horizontal sections for tumor extension also allows for a greater degree of tissue conservation than other modalities.^6,25 Mohs micrographic surgery is particularly useful for tumors of the midface, aggressive histologic subtype (eg, morpheic, infiltrating, basosquamous, micronodular), deep invasion, and perineural spread.^6,8,18,25 In a large review of 3 studies including a total of 7670 patients with primary BCC treated by MMS, Rowe et al²⁶ reported a 5-year recurrence rate of 1.0%, which was 8.7 times less than the weighted average of all non-MMS modalities. Similarly, in a large prospective review by Leibovitch et al,¹⁸ the 5-year recurrence rate of BCC treated with MMS was 1.4% in primary cases and 4.0% in previously recurrent cases.¹⁸ They reported that the main predictors of recurrence included longer tumor duration, more levels of excision required to obtain clear margins, notable subclinical extension, and prior recurrence. Interestingly, tumor and postexcision defect size did not predict recurrence.¹⁸ Margin-controlled excision with MMS was associated with higher success rates than modalities based on clinical margins without histologic control (eg, surgical excision, electrocautery, curettage) and potentially incomplete excision.^12,18

Although MMS has been demonstrated to have a high success rate, it has relative disadvantages. Tumors that are multicentric or have indistinct borders are more difficult to treat with MMS, and cure rates with MMS have been shown to decrease with increasing tumor diameter.^13,25 For example, reported cure rates are greater than 99% for MMS in BCCs less than 2 cm in diameter compared to 98.6% for those between 2 and 3 cm, and only 90.5% for those greater than 3 cm.²⁷ Mohs micrographic surgery requires a highly trained surgeon and can be extremely time consuming and labor intensive, particularly with large and locally aggressive tumors.^6,25 Tumors that involve fat and cartilage require modifications to standardized processing techniques, and deep wounds involving muscle and bone create technical challenges in maintaining orientation.²⁵ In the past, MMS was more expensive than other treatment modalities; however, cost analyses have demonstrated a near-equal cost of MMS compared to surgical excision with permanent section control and lower cost as compared to radiation therapy for selected cases.²⁸

Surgical excision also is considered a highly effective treatment of primary BCC and is the most commonly used treatment modality for BCC.^5,18,29 In this procedure, the peripheral and deep margins of excised tissue can be examined by a pathologist.⁶ Telfer et al⁶ recommended SE as the preferable treatment of choice for both large and small tumors in low-risk sites (ie, those that do not include the face) with nodular histology, tumors with morpheic histology in low-risk sites, and small (<2 cm) superficial tumors in high-risk sites. It is recommended that the size of surgical margins correlate with the likelihood of the presence of subclinical tumor extensions. Larger and morpheic-type BCCs require wider margins to achieve complete excision. In these cases, a 3-mm margin yields only a 66% cure rate, while 5-mm margins yield an 82% cure rate and 13- to 15-mm margins yield cure rates higher than 95%.^6,29,30 In a series examining recurrence rates of primary BCC, Rowe et al²⁶ reviewed 10 studies (2606 patients treated by SE) and calculated a 5-year recurrence rate of 10.1%. Silverman et al³¹ reviewed 5-year recurrence rates in 588 cases of BCC treated with SE. They concluded that BCC on the neck, trunk, arms, and legs of any size may be effectively treated with this modality, with 1 case of recurrence among 187 cases (0.5% recurrence rate). Multivariate analysis identified 2 independent risk factors for recurrence: anatomic site (head) and patient sex (male). Analysis of BCCs on the head distinct from other body sites demonstrated a moderately significant trend (P=.196) of increasing diameter with increasing recurrence rates. Age at treatment, duration of lesion, and length of treatment were not significantly associated with an increased risk of recurrence.³¹ Similarly, a review of 1417 cases of BCC by Dubin and Kopf²¹ demonstrated an increased risk with tumors located on the head and larger lesions.

RELATED ARTICLE: Basal Cell Carcinoma: Analysis of Factors Associated With Incomplete Excision

Radiotherapy (RT) is a commonly employed nonsurgical approach to management. Its use has been declining in recent years due to relative disadvantages and side effects. Similar to MMS, it can be extremely effective for carefully selected patients.^11,31 Radiotherapy is most effective for use with aggressive, rapidly growing BCC subtypes that are more sensitive to radiation, as replicating cells undergo mitotic death when radiation is applied.¹⁵ Radiotherapy is considered a viable option for patients who are not candidates for surgery, tumors in locations difficult to access for SE, and for rare unresectable tumors as a primary therapy.^5,11 In a randomized comparison between RT and SE approaches to the treatment of primary BCCs on the face, RT was found to be inferior to SE both in efficacy (4-year recurrence rate, 7.5% vs 0.7%) and cosmesis (rate of good results, 69% vs 87%).³²

The major disadvantages of RT as compared to other treatment modalities such as MMS or SE are the lack of control at margins and compromised inferior cosmetic outcomes. Hair loss, hyperpigmentation or hypopigmentation, telangiectasia, keloids, cutaneous necrosis, and RT-induced dermatitis have been reported as side effects of RT.^6,11,32-34 Other disadvantages of RT include the inconvenience of multiple visits to the hospital for treatment, and high cost as compared to other modalities such as MMS.³⁵ Finally, use of RT even for relatively benign disease has been linked to an increased risk for both squamous cell carcinoma, BCC, and sarcomas.^15,36

Vismodegib is an oral drug approved by the US Food and Drug Administration in 2012 for the treatment of locally advanced BCC. It is a first-in-class small-molecule systemic inhibitor of the intracellular hedgehog signaling pathway, which has been implicated in the growth and development of several types of cancer, including BCC.^36-38 Most patients with BCC carry loss-of-function mutations that affect PTCH1 and result in unregulated reactivation of the hedgehog pathway and uncontrolled cell growth.^38-40 Vismodegib is a small molecule that selectively deactivates the hedgehog pathway. It currently is indicated for the treatment of metastatic BCC or patients with locally advanced BCCs who are not candidates for SE or RT.^38-41 An open-label nonrandomized phase 2 study by Sekulic et al⁴² evaluated the effectiveness of vismodegib for treatment of metastatic or inoperable BCCs. In 33 patients with metastatic BCCs, the response rate was 30% (10/33) with a 9.5-month median progression-free survival. All responses were partial, with 73% (24/33) showing tumor shrinkage. In 63 patients with locally advanced BCCs, the response rate was 43% (27/63). Most patients demonstrated visible reductions in tumor size and improvement in appearance, but 13 patients (21%) in this group were noted to have a complete response (ie, absence of residual BCC on biopsy). Both cohorts had a median response time of 7.6 months.⁴²

Conclusion

Our patient presented with an extremely large and ulcerating lesion on the upper back that met the criteria for classification as a high-risk tumor. In light of the tumor location and size as well as the involvement of deep tissues and muscles, we elected to pursue SE for management. This modality proved to be extremely effective, and the patient continues to be free of residual or recurrent BCC more than 36 months after surgery. Two large systematic reviews lend support to this management approach and report excellent outcomes. In a review article by Rubin et al,⁵ SE was shown to provide cure rates greater than 99% for BCC lesions of any size on the neck, trunk, and extremities. Moreover, Thissen et al⁴³ performed a systematic meta-analysis of 18 studies reporting recurrence rates of primary BCC after treatment with various modalities and concluded that when surgery is not contraindicated, SE is the treatment of choice for nodular and superficial BCC. Both groups agree in their recommendations that MMS should be used for BCCs in cosmetically compromised zones (eg, midface), sites where tissue sparing is essential, aggressive growth patterns (eg, perineural invasion, morpheaform histology), and when high risk of recurrence is unacceptable.^5,43 In contrast, MMS is not recommended for tumors of large diameter or with indistinct borders due to decreased cure rates.^13,25,27 Vismodegib is an interesting new option in development for management of metastatic and aggressive nonresectable BCCs. It was not an option in our patient. Although consideration for use of vismodegib as a neoadjuvant treatment to shrink the tumor prior to surgery is reasonable, the decision to proceed directly with SE proved to be the superior option for our patient.

The number of patients who undergo total knee arthroplasty (TKA) and total hip arthroplasty (THA) procedures has significantly increased over the past 2 to 3 decades. As life expectancy in the U.S. increases and medical advances allow patients with preexisting conditions to successfully undergo joint replacements, the demand for these procedures is expected to grow.¹ In 2010, the CDC estimated that 719,000 patients underwent TKA procedures and 332,000 patients underwent THA procedures in the U.S.² Kurtz and colleagues have projected that by 2030 the annual number of TKA procedures will increase to 3.5 million and the number of THA procedures will increase to 572,000.¹

Although becoming more prevalent, these procedures are still associated with considerable intra- and postoperative blood loss that may lead to complications and blood transfusions.³ Previous studies have shown that perioperative anemia and red blood cell transfusions are associated with negative outcomes, including increased health care resource utilization; length of hospitalization; pulmonary, septic, wound, or thromboembolic complications; and mortality.^4,5

In order to prevent excessive blood loss during TKA and THA procedures, antifibrinolytic agents, such as tranexamic acid, have been used. Tranexamic acid is a synthetic form of lysine that binds to the lysine-binding sites on plasminogen and slows the conversion of plasminogen to plasmin. This interaction inhibits fibrinolysis and theoretically decreases bleeding.⁶ Because tranexamic acid is an antifibrinolytic, its mechanism of action has raised concerns that it could increase the risk of clotting complications, such as venous thromboembolism and myocardial infarction.⁷

Several published meta-analyses and systematic reviews have shown that tranexamic acid reduces blood loss in patients undergoing orthopedic surgery. Despite positive results, many study authors have acknowledged limitations in their analyses, such as heterogeneity of study results, small trial size, and varied dosing strategies.^3,7-12 There is no FDA-approved tranexamic acid dosing strategy for orthopedic procedures; therefore, its use in TKA and THA procedures is off label. This lack of guidance results in the medication being used at varied doses, timing of doses, and routes of administration with no clear dosing strategy showing the best outcomes.

Tranexamic acid was first used in TKA and THA surgical procedures at the Sioux Falls VA Health Care System (SFVAHCS) in South Dakota in October 2012. The dose used during these procedures was 1 g IV at first surgical incision and 1 g IV at incision closure. The objective of this study was to determine whether this tranexamic acid dosing strategy utilized at SFVAHCS safely improved outcomes related to blood loss.

Methods

A single-center retrospective chart review was performed on all patients who underwent TKA and THA procedures by 4 orthopedic surgeons between January 2010 and August 2015 at SFVAHCS. This study received approval by the local institutional review board and research and development committee in September 2015.

Patients were included in the study if they were aged ≥ 18 years and underwent primary unilateral TKA or THA procedures during the study time frame. Patients were excluded if they underwent bilateral or revision TKA or THA procedures, did not have recorded blood loss measurements during and/or after the procedure, or did not receive tranexamic acid between October 2012 and August 2015 at the standard dosing strategy utilized at SFVAHCS.

Patients who underwent surgery between January 2010 and October 2012 and did not receive tranexamic acid were included in the control groups. The treatment groups contained patients who underwent surgery between October 2012 and August 2015 and received tranexamic acid at the standard SFVAHCS dosing strategy. Patients in the control and treatment groups were divided and compared with patients who underwent the same type of surgery.

The primary endpoint of this study was total blood loss, which included intraoperative and postoperative blood loss. Intraoperative blood loss was measured by a suctioning device that the surgical physician’s assistant used to keep the surgical site clear of bodily fluids. The suctioning device collected blood as well as irrigation fluids used throughout the surgical procedure. The volume of irrigation fluids used during the procedure was subtracted from the total volume collected by the suctioning device to estimate the total blood volume lost during surgery. Sponges and other surgical materials that may have collected blood were not included in the intraoperative blood loss calculation. Postoperative blood loss was collected by a drain that was placed in the surgical site prior to incision closure. The drain collected postoperative blood loss until it was removed 1 day after surgery.

The secondary endpoints for the study were changes in hemoglobin (Hgb) and hematocrit (Hct) from before surgery to after surgery. These changes were calculated by subtracting the lowest measured postoperative Hgb or Hct level within 21 days postsurgery from the closest measured Hgb or Hct level obtained presurgery.

Follow-up appointments were routinely conducted 2 weeks after surgery, so the 21-day time frame would include any laboratory results drawn at these appointments. Other secondary endpoints included the number of patients receiving at least 1 blood transfusion during hospitalization and the number of patients experiencing clotting complications within 30 days of surgery. Postoperative and progress notes were reviewed by a single study investigator in order to record blood transfusions and clotting complications.

All patients who underwent TKA or THA procedures were instructed to stop taking antiplatelet agents 7 days prior to surgery and warfarin 5 days prior to surgery. If patients were determined to be at high risk for thromboembolic complications following warfarin discontinuation, therapeutic doses of low-molecular weight heparin or unfractionated heparin were used as a bridging therapy pre- and postsurgery. Enoxaparin 30 mg twice daily was started the day after surgery in all patients not previously on warfarin therapy prior to surgery to prevent clotting complications. If a patient was on warfarin therapy prior to the procedure but not considered to be at high risk of thromboembolic complications by the surgeon, warfarin was restarted after surgery, and enoxaparin 30 mg twice daily was used until therapeutic international normalized ratio values were obtained. If the patient had ongoing bleeding after the procedure or was determined to be at high risk for bleeding complications, the provider may have delayed anticoagulant use.

Some patients who underwent TKA or THA procedures during the study time frame received periarticular pain injections during surgery. These pain injections included a combination of ropivacaine 200 mg, ketorolac 30 mg, epinephrine 0.5 mg, and clonidine 0.08 mg and were compounded in a sterile mixture with normal saline. Several injections of this mixture were administered into the surgical site to reduce postoperative pain. These periarticular pain injections were first implemented into TKA and THA procedures in August 2012 and were used in patients at the surgeon’s discretion.

Baseline characteristics were analyzed using a chi-square test for categoric variables and an unpaired t test for continuous variables to determine whether any differences were present. Total blood loss, change in Hgb, and change in Hct were analyzed using an unpaired t test. Patients receiving at least 1 blood transfusion during hospitalization and patients experiencing a clotting complication were analyzed using a chi-square test. P values < .05 were considered to indicate statistical significance. Descriptive statistics were calculated using Microsoft Excel (Redmond, WA), and GraphPad Prism (La Jolla, CA) was used for all statistical analyses.

Results

Initially, a total of 443 TKA patients and 111 THA patients were reviewed. Of these patients, 418 TKA patients and 100 THA patients met the inclusion criteria. Due to the retrospective design of this study, not all of the baseline characteristics were equal between groups (Table 1). Most notably, the number of patients who received the periarticular pain injection and the distribution of surgeons performing the procedures were different between groups in both the TKA and THA procedures.

Baseline Hgb levels were not found to be different between groups in either type of procedure; however, the baseline Hct levels of patients undergoing TKA who received tranexamic acid were found to be statistically higher when compared with those who did not receive tranexamic acid. Other baseline characteristics with statistically higher values included average weight and BMI in patients who received tranexamic acid and underwent THA and serum creatinine in patients who did not receive tranexamic acid and underwent TKA.

In the primary analysis (Tables 2 and 3), the mean estimated total blood loss in TKA patients was lower in patients who received tranexamic acid than it was in the control group (339.4 mL vs 457.4 mL, P < .001). Patients who underwent THA receiving tranexamic acid similarly had significantly less total blood loss than that of the control group (419.7 mL vs 585.7 mL, P < .001). Consistent with previous studies, patients undergoing TKA procedures in the treatment group when compared to the control group, respectively, were likely to have more blood loss postoperatively (275.9 mL vs 399.7 mL) than intraoperatively (63.5 mL vs 57.7 mL) regardless of tranexamic acid administration.⁶ On the other hand, patients who had undergone THA were more likely to experience more intraoperative blood loss (281.6 mL in treatment group vs 328.9 mL in control group) than postoperative blood loss (138.1 mL in treatment group vs 256.8 mL in control group) regardless of tranexamic acid administration.

In the secondary analysis, the change between preoperative and postoperative Hgb and Hct had results consistent with the total blood loss results. Patients receiving tranexamic acid in TKA procedures had a lower decrease in Hgb compared with the control group (3.3 mg/dL vs 4.0 mg/dL, P < .001). Similarly, patients undergoing TKA who received tranexamic acid had a smaller decrease in Hct than that of the control group (9.4% vs 11.1%, P < .001). Consistent with the TKA procedure results, patients undergoing THA who received tranexamic acid had a smaller decrease in Hgb (3.6 mg/dL vs 4.7 mg/dL, P < .001) and Hct (10.5% vs 13.0%, P = .0012) than that of the control group.

Patients who did not receive tranexamic acid were more likely to require at least 1 blood transfusion than were patients who received tranexamic acid in TKA (14 patients vs 0 patients, P = .0005) and THA procedures (8 patients vs 2 patients, P = .019). Despite the theoretically increased likelihood of clotting complications with tranexamic acid, no significant differences were observed between the treatment and control groups in either TKA (0 vs 4, P = .065) or THA (1 vs 0, P = .363) procedures.

Discussion

Patients undergoing total joint arthroplasty are at risk for significant blood loss with a potential need for postoperative blood transfusions.^6,13 The use of tranexamic acid during these procedures offers a possible solution to decrease blood loss and minimize blood transfusions. This study retrospectively evaluated whether tranexamic acid safely decreased blood loss and the need for blood transfusions at SFVAHCS with the dosing strategy of 1 g IV at first incision and 1 g IV at incision closure.

Patients who received tranexamic acid in TKA and THA procedures had significantly less blood loss than did patients who did not receive tranexamic acid. Patients receiving tranexamic acid also had a significantly lower change from preoperative to postoperative Hgb and Hct levels than did patients who did not receive tranexamic acid in TKA and THA procedures. In addition to decreasing blood loss, the tranexamic acid groups had significantly fewer patients who required blood transfusions than that of the control groups.

This reduction in blood transfusions should be considered clinically significant. Blood transfusions require substantial health care resource utilization and may cause complications in recipients.³ There was no clear association between tranexamic acid and clotting complications in this study, which may suggest that this risk is theoretical. However, larger prospective studies would be needed to further examine this potential risk.

Even though baseline Hct levels were found to be significantly different between the tranexamic acid group and the control group for patients who underwent TKA, medical record documentation indicated that the determination whether postoperative blood transfusions were needed was based primarily on Hgb levels. Baseline Hgb levels were found not to be significantly different between the tranexamic acid and control groups for either TKA or THA procedures. This suggests that at baseline the tranexamic acid and control groups had the same risk of reaching the Hgb threshold where blood transfusions would be required.

There was a significant difference in the proportion of patients receiving the periarticular pain injection of ropivacaine, ketorolac, epinephrine, and clonidine between the groups who received tranexamic acid and those who did not. Originally, this baseline characteristic was theorized to be a major confounder in the primary and secondary analyses because epinephrine is a vasoconstrictor and ketorolac is a reversible antiplatelet agent. However, Vendittoli and colleagues showed that patients receiving these periarticular pain injections during surgery actually had greater total blood loss than did patients who did not receive the injections, although this comparison did not reach statistical significance.¹⁴ The Vendittoli and colleagues results suggest that the pain injections did not confound the primary and secondary analyses by aiding in the process of reducing blood loss in these procedures.

Limitations

There are several limitations for extrapolating the results from this study to the general population. Due to the retrospective study design, there was no way to actively control potentially confounding variables during the TKA and THA procedures. Surgeons and surgery teams likely had slightly different techniques and protocols during and after surgery. Several baseline characteristics were not equal between patients who received tranexamic acid and those who did not. Therefore, it is unknown whether these baseline characteristics affected the results of this study. Postoperative anticoagulant use was not recorded and may have differed between study groups, depending on the patient’s risk of thromboembolic complications; however, the drains that collected blood loss were removed prior to the first dose of enoxaparin, which was administered the day after surgery.

Another limitation is that the method of measuring blood loss during and after the procedure was imprecise. Blood not suctioned through the suctioning device during surgery or not collected in the drain after surgery was not measured and may have increased the total blood loss. Hemoglobin and Hct levels also are sensitive to intravascular volume changes. If a patient required more IV fluids during or after a procedure, the fluids may have lowered the Hgb and/or Hct levels by dilution.

Conclusion

This study suggests that using tranexamic acid at a dose of 1 g IV at first incision and 1 g IV at incision closure safely and effectively reduced blood loss and the need for transfusions in patients undergoing TKA and THA procedures at SFVAHCS. Further prospective studies are needed to compare different tranexamic dosing strategies to minimize blood loss during these procedures. ˜

Acknowledgments
This study is the result of work supported with resources and the use of facilities at the Sioux Falls VA Health Care System in South Dakota.

The number of patients who undergo total knee arthroplasty (TKA) and total hip arthroplasty (THA) procedures has significantly increased over the past 2 to 3 decades. As life expectancy in the U.S. increases and medical advances allow patients with preexisting conditions to successfully undergo joint replacements, the demand for these procedures is expected to grow.¹ In 2010, the CDC estimated that 719,000 patients underwent TKA procedures and 332,000 patients underwent THA procedures in the U.S.² Kurtz and colleagues have projected that by 2030 the annual number of TKA procedures will increase to 3.5 million and the number of THA procedures will increase to 572,000.¹

Although becoming more prevalent, these procedures are still associated with considerable intra- and postoperative blood loss that may lead to complications and blood transfusions.³ Previous studies have shown that perioperative anemia and red blood cell transfusions are associated with negative outcomes, including increased health care resource utilization; length of hospitalization; pulmonary, septic, wound, or thromboembolic complications; and mortality.^4,5

In order to prevent excessive blood loss during TKA and THA procedures, antifibrinolytic agents, such as tranexamic acid, have been used. Tranexamic acid is a synthetic form of lysine that binds to the lysine-binding sites on plasminogen and slows the conversion of plasminogen to plasmin. This interaction inhibits fibrinolysis and theoretically decreases bleeding.⁶ Because tranexamic acid is an antifibrinolytic, its mechanism of action has raised concerns that it could increase the risk of clotting complications, such as venous thromboembolism and myocardial infarction.⁷

Several published meta-analyses and systematic reviews have shown that tranexamic acid reduces blood loss in patients undergoing orthopedic surgery. Despite positive results, many study authors have acknowledged limitations in their analyses, such as heterogeneity of study results, small trial size, and varied dosing strategies.^3,7-12 There is no FDA-approved tranexamic acid dosing strategy for orthopedic procedures; therefore, its use in TKA and THA procedures is off label. This lack of guidance results in the medication being used at varied doses, timing of doses, and routes of administration with no clear dosing strategy showing the best outcomes.

Tranexamic acid was first used in TKA and THA surgical procedures at the Sioux Falls VA Health Care System (SFVAHCS) in South Dakota in October 2012. The dose used during these procedures was 1 g IV at first surgical incision and 1 g IV at incision closure. The objective of this study was to determine whether this tranexamic acid dosing strategy utilized at SFVAHCS safely improved outcomes related to blood loss.

Methods

A single-center retrospective chart review was performed on all patients who underwent TKA and THA procedures by 4 orthopedic surgeons between January 2010 and August 2015 at SFVAHCS. This study received approval by the local institutional review board and research and development committee in September 2015.

Patients were included in the study if they were aged ≥ 18 years and underwent primary unilateral TKA or THA procedures during the study time frame. Patients were excluded if they underwent bilateral or revision TKA or THA procedures, did not have recorded blood loss measurements during and/or after the procedure, or did not receive tranexamic acid between October 2012 and August 2015 at the standard dosing strategy utilized at SFVAHCS.

Patients who underwent surgery between January 2010 and October 2012 and did not receive tranexamic acid were included in the control groups. The treatment groups contained patients who underwent surgery between October 2012 and August 2015 and received tranexamic acid at the standard SFVAHCS dosing strategy. Patients in the control and treatment groups were divided and compared with patients who underwent the same type of surgery.

The primary endpoint of this study was total blood loss, which included intraoperative and postoperative blood loss. Intraoperative blood loss was measured by a suctioning device that the surgical physician’s assistant used to keep the surgical site clear of bodily fluids. The suctioning device collected blood as well as irrigation fluids used throughout the surgical procedure. The volume of irrigation fluids used during the procedure was subtracted from the total volume collected by the suctioning device to estimate the total blood volume lost during surgery. Sponges and other surgical materials that may have collected blood were not included in the intraoperative blood loss calculation. Postoperative blood loss was collected by a drain that was placed in the surgical site prior to incision closure. The drain collected postoperative blood loss until it was removed 1 day after surgery.

The secondary endpoints for the study were changes in hemoglobin (Hgb) and hematocrit (Hct) from before surgery to after surgery. These changes were calculated by subtracting the lowest measured postoperative Hgb or Hct level within 21 days postsurgery from the closest measured Hgb or Hct level obtained presurgery.

Follow-up appointments were routinely conducted 2 weeks after surgery, so the 21-day time frame would include any laboratory results drawn at these appointments. Other secondary endpoints included the number of patients receiving at least 1 blood transfusion during hospitalization and the number of patients experiencing clotting complications within 30 days of surgery. Postoperative and progress notes were reviewed by a single study investigator in order to record blood transfusions and clotting complications.

All patients who underwent TKA or THA procedures were instructed to stop taking antiplatelet agents 7 days prior to surgery and warfarin 5 days prior to surgery. If patients were determined to be at high risk for thromboembolic complications following warfarin discontinuation, therapeutic doses of low-molecular weight heparin or unfractionated heparin were used as a bridging therapy pre- and postsurgery. Enoxaparin 30 mg twice daily was started the day after surgery in all patients not previously on warfarin therapy prior to surgery to prevent clotting complications. If a patient was on warfarin therapy prior to the procedure but not considered to be at high risk of thromboembolic complications by the surgeon, warfarin was restarted after surgery, and enoxaparin 30 mg twice daily was used until therapeutic international normalized ratio values were obtained. If the patient had ongoing bleeding after the procedure or was determined to be at high risk for bleeding complications, the provider may have delayed anticoagulant use.

Some patients who underwent TKA or THA procedures during the study time frame received periarticular pain injections during surgery. These pain injections included a combination of ropivacaine 200 mg, ketorolac 30 mg, epinephrine 0.5 mg, and clonidine 0.08 mg and were compounded in a sterile mixture with normal saline. Several injections of this mixture were administered into the surgical site to reduce postoperative pain. These periarticular pain injections were first implemented into TKA and THA procedures in August 2012 and were used in patients at the surgeon’s discretion.

Baseline characteristics were analyzed using a chi-square test for categoric variables and an unpaired t test for continuous variables to determine whether any differences were present. Total blood loss, change in Hgb, and change in Hct were analyzed using an unpaired t test. Patients receiving at least 1 blood transfusion during hospitalization and patients experiencing a clotting complication were analyzed using a chi-square test. P values < .05 were considered to indicate statistical significance. Descriptive statistics were calculated using Microsoft Excel (Redmond, WA), and GraphPad Prism (La Jolla, CA) was used for all statistical analyses.

Results

Initially, a total of 443 TKA patients and 111 THA patients were reviewed. Of these patients, 418 TKA patients and 100 THA patients met the inclusion criteria. Due to the retrospective design of this study, not all of the baseline characteristics were equal between groups (Table 1). Most notably, the number of patients who received the periarticular pain injection and the distribution of surgeons performing the procedures were different between groups in both the TKA and THA procedures.

Baseline Hgb levels were not found to be different between groups in either type of procedure; however, the baseline Hct levels of patients undergoing TKA who received tranexamic acid were found to be statistically higher when compared with those who did not receive tranexamic acid. Other baseline characteristics with statistically higher values included average weight and BMI in patients who received tranexamic acid and underwent THA and serum creatinine in patients who did not receive tranexamic acid and underwent TKA.

In the primary analysis (Tables 2 and 3), the mean estimated total blood loss in TKA patients was lower in patients who received tranexamic acid than it was in the control group (339.4 mL vs 457.4 mL, P < .001). Patients who underwent THA receiving tranexamic acid similarly had significantly less total blood loss than that of the control group (419.7 mL vs 585.7 mL, P < .001). Consistent with previous studies, patients undergoing TKA procedures in the treatment group when compared to the control group, respectively, were likely to have more blood loss postoperatively (275.9 mL vs 399.7 mL) than intraoperatively (63.5 mL vs 57.7 mL) regardless of tranexamic acid administration.⁶ On the other hand, patients who had undergone THA were more likely to experience more intraoperative blood loss (281.6 mL in treatment group vs 328.9 mL in control group) than postoperative blood loss (138.1 mL in treatment group vs 256.8 mL in control group) regardless of tranexamic acid administration.

In the secondary analysis, the change between preoperative and postoperative Hgb and Hct had results consistent with the total blood loss results. Patients receiving tranexamic acid in TKA procedures had a lower decrease in Hgb compared with the control group (3.3 mg/dL vs 4.0 mg/dL, P < .001). Similarly, patients undergoing TKA who received tranexamic acid had a smaller decrease in Hct than that of the control group (9.4% vs 11.1%, P < .001). Consistent with the TKA procedure results, patients undergoing THA who received tranexamic acid had a smaller decrease in Hgb (3.6 mg/dL vs 4.7 mg/dL, P < .001) and Hct (10.5% vs 13.0%, P = .0012) than that of the control group.

Patients who did not receive tranexamic acid were more likely to require at least 1 blood transfusion than were patients who received tranexamic acid in TKA (14 patients vs 0 patients, P = .0005) and THA procedures (8 patients vs 2 patients, P = .019). Despite the theoretically increased likelihood of clotting complications with tranexamic acid, no significant differences were observed between the treatment and control groups in either TKA (0 vs 4, P = .065) or THA (1 vs 0, P = .363) procedures.

Discussion

Patients undergoing total joint arthroplasty are at risk for significant blood loss with a potential need for postoperative blood transfusions.^6,13 The use of tranexamic acid during these procedures offers a possible solution to decrease blood loss and minimize blood transfusions. This study retrospectively evaluated whether tranexamic acid safely decreased blood loss and the need for blood transfusions at SFVAHCS with the dosing strategy of 1 g IV at first incision and 1 g IV at incision closure.

Patients who received tranexamic acid in TKA and THA procedures had significantly less blood loss than did patients who did not receive tranexamic acid. Patients receiving tranexamic acid also had a significantly lower change from preoperative to postoperative Hgb and Hct levels than did patients who did not receive tranexamic acid in TKA and THA procedures. In addition to decreasing blood loss, the tranexamic acid groups had significantly fewer patients who required blood transfusions than that of the control groups.

This reduction in blood transfusions should be considered clinically significant. Blood transfusions require substantial health care resource utilization and may cause complications in recipients.³ There was no clear association between tranexamic acid and clotting complications in this study, which may suggest that this risk is theoretical. However, larger prospective studies would be needed to further examine this potential risk.

Even though baseline Hct levels were found to be significantly different between the tranexamic acid group and the control group for patients who underwent TKA, medical record documentation indicated that the determination whether postoperative blood transfusions were needed was based primarily on Hgb levels. Baseline Hgb levels were found not to be significantly different between the tranexamic acid and control groups for either TKA or THA procedures. This suggests that at baseline the tranexamic acid and control groups had the same risk of reaching the Hgb threshold where blood transfusions would be required.

There was a significant difference in the proportion of patients receiving the periarticular pain injection of ropivacaine, ketorolac, epinephrine, and clonidine between the groups who received tranexamic acid and those who did not. Originally, this baseline characteristic was theorized to be a major confounder in the primary and secondary analyses because epinephrine is a vasoconstrictor and ketorolac is a reversible antiplatelet agent. However, Vendittoli and colleagues showed that patients receiving these periarticular pain injections during surgery actually had greater total blood loss than did patients who did not receive the injections, although this comparison did not reach statistical significance.¹⁴ The Vendittoli and colleagues results suggest that the pain injections did not confound the primary and secondary analyses by aiding in the process of reducing blood loss in these procedures.

Limitations

There are several limitations for extrapolating the results from this study to the general population. Due to the retrospective study design, there was no way to actively control potentially confounding variables during the TKA and THA procedures. Surgeons and surgery teams likely had slightly different techniques and protocols during and after surgery. Several baseline characteristics were not equal between patients who received tranexamic acid and those who did not. Therefore, it is unknown whether these baseline characteristics affected the results of this study. Postoperative anticoagulant use was not recorded and may have differed between study groups, depending on the patient’s risk of thromboembolic complications; however, the drains that collected blood loss were removed prior to the first dose of enoxaparin, which was administered the day after surgery.

Another limitation is that the method of measuring blood loss during and after the procedure was imprecise. Blood not suctioned through the suctioning device during surgery or not collected in the drain after surgery was not measured and may have increased the total blood loss. Hemoglobin and Hct levels also are sensitive to intravascular volume changes. If a patient required more IV fluids during or after a procedure, the fluids may have lowered the Hgb and/or Hct levels by dilution.

Conclusion

This study suggests that using tranexamic acid at a dose of 1 g IV at first incision and 1 g IV at incision closure safely and effectively reduced blood loss and the need for transfusions in patients undergoing TKA and THA procedures at SFVAHCS. Further prospective studies are needed to compare different tranexamic dosing strategies to minimize blood loss during these procedures. ˜

Acknowledgments
This study is the result of work supported with resources and the use of facilities at the Sioux Falls VA Health Care System in South Dakota.

The number of patients who undergo total knee arthroplasty (TKA) and total hip arthroplasty (THA) procedures has significantly increased over the past 2 to 3 decades. As life expectancy in the U.S. increases and medical advances allow patients with preexisting conditions to successfully undergo joint replacements, the demand for these procedures is expected to grow.¹ In 2010, the CDC estimated that 719,000 patients underwent TKA procedures and 332,000 patients underwent THA procedures in the U.S.² Kurtz and colleagues have projected that by 2030 the annual number of TKA procedures will increase to 3.5 million and the number of THA procedures will increase to 572,000.¹

Although becoming more prevalent, these procedures are still associated with considerable intra- and postoperative blood loss that may lead to complications and blood transfusions.³ Previous studies have shown that perioperative anemia and red blood cell transfusions are associated with negative outcomes, including increased health care resource utilization; length of hospitalization; pulmonary, septic, wound, or thromboembolic complications; and mortality.^4,5

In order to prevent excessive blood loss during TKA and THA procedures, antifibrinolytic agents, such as tranexamic acid, have been used. Tranexamic acid is a synthetic form of lysine that binds to the lysine-binding sites on plasminogen and slows the conversion of plasminogen to plasmin. This interaction inhibits fibrinolysis and theoretically decreases bleeding.⁶ Because tranexamic acid is an antifibrinolytic, its mechanism of action has raised concerns that it could increase the risk of clotting complications, such as venous thromboembolism and myocardial infarction.⁷

Several published meta-analyses and systematic reviews have shown that tranexamic acid reduces blood loss in patients undergoing orthopedic surgery. Despite positive results, many study authors have acknowledged limitations in their analyses, such as heterogeneity of study results, small trial size, and varied dosing strategies.^3,7-12 There is no FDA-approved tranexamic acid dosing strategy for orthopedic procedures; therefore, its use in TKA and THA procedures is off label. This lack of guidance results in the medication being used at varied doses, timing of doses, and routes of administration with no clear dosing strategy showing the best outcomes.

Tranexamic acid was first used in TKA and THA surgical procedures at the Sioux Falls VA Health Care System (SFVAHCS) in South Dakota in October 2012. The dose used during these procedures was 1 g IV at first surgical incision and 1 g IV at incision closure. The objective of this study was to determine whether this tranexamic acid dosing strategy utilized at SFVAHCS safely improved outcomes related to blood loss.

Methods

A single-center retrospective chart review was performed on all patients who underwent TKA and THA procedures by 4 orthopedic surgeons between January 2010 and August 2015 at SFVAHCS. This study received approval by the local institutional review board and research and development committee in September 2015.

Patients were included in the study if they were aged ≥ 18 years and underwent primary unilateral TKA or THA procedures during the study time frame. Patients were excluded if they underwent bilateral or revision TKA or THA procedures, did not have recorded blood loss measurements during and/or after the procedure, or did not receive tranexamic acid between October 2012 and August 2015 at the standard dosing strategy utilized at SFVAHCS.

Patients who underwent surgery between January 2010 and October 2012 and did not receive tranexamic acid were included in the control groups. The treatment groups contained patients who underwent surgery between October 2012 and August 2015 and received tranexamic acid at the standard SFVAHCS dosing strategy. Patients in the control and treatment groups were divided and compared with patients who underwent the same type of surgery.

The primary endpoint of this study was total blood loss, which included intraoperative and postoperative blood loss. Intraoperative blood loss was measured by a suctioning device that the surgical physician’s assistant used to keep the surgical site clear of bodily fluids. The suctioning device collected blood as well as irrigation fluids used throughout the surgical procedure. The volume of irrigation fluids used during the procedure was subtracted from the total volume collected by the suctioning device to estimate the total blood volume lost during surgery. Sponges and other surgical materials that may have collected blood were not included in the intraoperative blood loss calculation. Postoperative blood loss was collected by a drain that was placed in the surgical site prior to incision closure. The drain collected postoperative blood loss until it was removed 1 day after surgery.

The secondary endpoints for the study were changes in hemoglobin (Hgb) and hematocrit (Hct) from before surgery to after surgery. These changes were calculated by subtracting the lowest measured postoperative Hgb or Hct level within 21 days postsurgery from the closest measured Hgb or Hct level obtained presurgery.

Follow-up appointments were routinely conducted 2 weeks after surgery, so the 21-day time frame would include any laboratory results drawn at these appointments. Other secondary endpoints included the number of patients receiving at least 1 blood transfusion during hospitalization and the number of patients experiencing clotting complications within 30 days of surgery. Postoperative and progress notes were reviewed by a single study investigator in order to record blood transfusions and clotting complications.

All patients who underwent TKA or THA procedures were instructed to stop taking antiplatelet agents 7 days prior to surgery and warfarin 5 days prior to surgery. If patients were determined to be at high risk for thromboembolic complications following warfarin discontinuation, therapeutic doses of low-molecular weight heparin or unfractionated heparin were used as a bridging therapy pre- and postsurgery. Enoxaparin 30 mg twice daily was started the day after surgery in all patients not previously on warfarin therapy prior to surgery to prevent clotting complications. If a patient was on warfarin therapy prior to the procedure but not considered to be at high risk of thromboembolic complications by the surgeon, warfarin was restarted after surgery, and enoxaparin 30 mg twice daily was used until therapeutic international normalized ratio values were obtained. If the patient had ongoing bleeding after the procedure or was determined to be at high risk for bleeding complications, the provider may have delayed anticoagulant use.

Some patients who underwent TKA or THA procedures during the study time frame received periarticular pain injections during surgery. These pain injections included a combination of ropivacaine 200 mg, ketorolac 30 mg, epinephrine 0.5 mg, and clonidine 0.08 mg and were compounded in a sterile mixture with normal saline. Several injections of this mixture were administered into the surgical site to reduce postoperative pain. These periarticular pain injections were first implemented into TKA and THA procedures in August 2012 and were used in patients at the surgeon’s discretion.

Baseline characteristics were analyzed using a chi-square test for categoric variables and an unpaired t test for continuous variables to determine whether any differences were present. Total blood loss, change in Hgb, and change in Hct were analyzed using an unpaired t test. Patients receiving at least 1 blood transfusion during hospitalization and patients experiencing a clotting complication were analyzed using a chi-square test. P values < .05 were considered to indicate statistical significance. Descriptive statistics were calculated using Microsoft Excel (Redmond, WA), and GraphPad Prism (La Jolla, CA) was used for all statistical analyses.

Results

Initially, a total of 443 TKA patients and 111 THA patients were reviewed. Of these patients, 418 TKA patients and 100 THA patients met the inclusion criteria. Due to the retrospective design of this study, not all of the baseline characteristics were equal between groups (Table 1). Most notably, the number of patients who received the periarticular pain injection and the distribution of surgeons performing the procedures were different between groups in both the TKA and THA procedures.

Baseline Hgb levels were not found to be different between groups in either type of procedure; however, the baseline Hct levels of patients undergoing TKA who received tranexamic acid were found to be statistically higher when compared with those who did not receive tranexamic acid. Other baseline characteristics with statistically higher values included average weight and BMI in patients who received tranexamic acid and underwent THA and serum creatinine in patients who did not receive tranexamic acid and underwent TKA.

In the primary analysis (Tables 2 and 3), the mean estimated total blood loss in TKA patients was lower in patients who received tranexamic acid than it was in the control group (339.4 mL vs 457.4 mL, P < .001). Patients who underwent THA receiving tranexamic acid similarly had significantly less total blood loss than that of the control group (419.7 mL vs 585.7 mL, P < .001). Consistent with previous studies, patients undergoing TKA procedures in the treatment group when compared to the control group, respectively, were likely to have more blood loss postoperatively (275.9 mL vs 399.7 mL) than intraoperatively (63.5 mL vs 57.7 mL) regardless of tranexamic acid administration.⁶ On the other hand, patients who had undergone THA were more likely to experience more intraoperative blood loss (281.6 mL in treatment group vs 328.9 mL in control group) than postoperative blood loss (138.1 mL in treatment group vs 256.8 mL in control group) regardless of tranexamic acid administration.

In the secondary analysis, the change between preoperative and postoperative Hgb and Hct had results consistent with the total blood loss results. Patients receiving tranexamic acid in TKA procedures had a lower decrease in Hgb compared with the control group (3.3 mg/dL vs 4.0 mg/dL, P < .001). Similarly, patients undergoing TKA who received tranexamic acid had a smaller decrease in Hct than that of the control group (9.4% vs 11.1%, P < .001). Consistent with the TKA procedure results, patients undergoing THA who received tranexamic acid had a smaller decrease in Hgb (3.6 mg/dL vs 4.7 mg/dL, P < .001) and Hct (10.5% vs 13.0%, P = .0012) than that of the control group.

Patients who did not receive tranexamic acid were more likely to require at least 1 blood transfusion than were patients who received tranexamic acid in TKA (14 patients vs 0 patients, P = .0005) and THA procedures (8 patients vs 2 patients, P = .019). Despite the theoretically increased likelihood of clotting complications with tranexamic acid, no significant differences were observed between the treatment and control groups in either TKA (0 vs 4, P = .065) or THA (1 vs 0, P = .363) procedures.

Discussion

Patients undergoing total joint arthroplasty are at risk for significant blood loss with a potential need for postoperative blood transfusions.^6,13 The use of tranexamic acid during these procedures offers a possible solution to decrease blood loss and minimize blood transfusions. This study retrospectively evaluated whether tranexamic acid safely decreased blood loss and the need for blood transfusions at SFVAHCS with the dosing strategy of 1 g IV at first incision and 1 g IV at incision closure.

Patients who received tranexamic acid in TKA and THA procedures had significantly less blood loss than did patients who did not receive tranexamic acid. Patients receiving tranexamic acid also had a significantly lower change from preoperative to postoperative Hgb and Hct levels than did patients who did not receive tranexamic acid in TKA and THA procedures. In addition to decreasing blood loss, the tranexamic acid groups had significantly fewer patients who required blood transfusions than that of the control groups.

This reduction in blood transfusions should be considered clinically significant. Blood transfusions require substantial health care resource utilization and may cause complications in recipients.³ There was no clear association between tranexamic acid and clotting complications in this study, which may suggest that this risk is theoretical. However, larger prospective studies would be needed to further examine this potential risk.

Even though baseline Hct levels were found to be significantly different between the tranexamic acid group and the control group for patients who underwent TKA, medical record documentation indicated that the determination whether postoperative blood transfusions were needed was based primarily on Hgb levels. Baseline Hgb levels were found not to be significantly different between the tranexamic acid and control groups for either TKA or THA procedures. This suggests that at baseline the tranexamic acid and control groups had the same risk of reaching the Hgb threshold where blood transfusions would be required.

There was a significant difference in the proportion of patients receiving the periarticular pain injection of ropivacaine, ketorolac, epinephrine, and clonidine between the groups who received tranexamic acid and those who did not. Originally, this baseline characteristic was theorized to be a major confounder in the primary and secondary analyses because epinephrine is a vasoconstrictor and ketorolac is a reversible antiplatelet agent. However, Vendittoli and colleagues showed that patients receiving these periarticular pain injections during surgery actually had greater total blood loss than did patients who did not receive the injections, although this comparison did not reach statistical significance.¹⁴ The Vendittoli and colleagues results suggest that the pain injections did not confound the primary and secondary analyses by aiding in the process of reducing blood loss in these procedures.

Limitations

There are several limitations for extrapolating the results from this study to the general population. Due to the retrospective study design, there was no way to actively control potentially confounding variables during the TKA and THA procedures. Surgeons and surgery teams likely had slightly different techniques and protocols during and after surgery. Several baseline characteristics were not equal between patients who received tranexamic acid and those who did not. Therefore, it is unknown whether these baseline characteristics affected the results of this study. Postoperative anticoagulant use was not recorded and may have differed between study groups, depending on the patient’s risk of thromboembolic complications; however, the drains that collected blood loss were removed prior to the first dose of enoxaparin, which was administered the day after surgery.

Another limitation is that the method of measuring blood loss during and after the procedure was imprecise. Blood not suctioned through the suctioning device during surgery or not collected in the drain after surgery was not measured and may have increased the total blood loss. Hemoglobin and Hct levels also are sensitive to intravascular volume changes. If a patient required more IV fluids during or after a procedure, the fluids may have lowered the Hgb and/or Hct levels by dilution.

Conclusion

This study suggests that using tranexamic acid at a dose of 1 g IV at first incision and 1 g IV at incision closure safely and effectively reduced blood loss and the need for transfusions in patients undergoing TKA and THA procedures at SFVAHCS. Further prospective studies are needed to compare different tranexamic dosing strategies to minimize blood loss during these procedures. ˜

Acknowledgments
This study is the result of work supported with resources and the use of facilities at the Sioux Falls VA Health Care System in South Dakota.