Clinical Review

IN THIS ARTICLE
• The “why” of endometriosis
• Environmental factors, estrogen, and endometriosis
• Is imaging useful?
• When is diagnostic laparoscopy clearly indicated?

CASE M.L. is a 32-year-old nulliparous woman who is referred to your office by her primary care provider for chronic pelvic pain. She reports severe dysmenorrhea as her main symptom, but she also mentions dyspareunia. She says these symptoms have been present for several years but have increased in intensity gradually. She asks what you consider to be the most likely diagnosis.

What potential diagnoses do you mention to her? And how do you identify the cause of her pain?

Although endometriosis—the presence of endometrial tissue outside the uterus—affects at least 5 million women of reproductive age in the United States alone, it can be a challenging diagnosis for several reasons.

“Endometriosis is a great masquerader,” says Linda Giudice, MD, PhD. “It presents with a variety of pain patterns, intensities, and triggers. It can also involve symptoms that overlap those of other disorders, including disorders of the gastrointestinal and urinary tracts.”

Although endometriosis falls within the differential diagnosis of chronic pelvic pain, “it is usually not high on the list in the primary care setting (adult and adolescent),” adds Dr. Giudice.

John R. Lue, MD, MPH, an author of the most recent practice bulletin on endometriosis from the American College of Obstetricians and Gynecologists,¹ sees the situation similarly.

“The main challenge in the diagnosis of endometriosis is that its presentation mimics other causes of chronic pelvic pain,” he says. “Pelvic pain due to endometriosis is usually chronic (lasting ≥ 6 months). It is associated with dysmenorrhea in 50% to 90% of cases, as well as with dyspareunia, deep pelvic pain, and lower abdominal pain with or without back and loin pain. The pain can occur unpredictably and intermittently throughout the menstrual cycle or it can be continuous. In addition, it can be dull, throbbing, or sharp and may be exacerbated by physical activity.^2,3 Up to 20% of women with endometriosis have concurrent pain conditions.”⁴

There are three types of endometriosis lesions—endometriomas, which affect the ovary; superficial lesions; and deep infiltrating endometriosis. Peritoneal lesions may vary widely in appearance. Some may be clear or red; others brown, blue, or black; and some may have a white, scar-like appearance. To identify this elusive disease, it is critical that the clinician be able to recognize its “many faces.”

Among other diseases of the female pelvis that have a relatively similar presentation, Dr. Lue adds, are pathologies of the
• Uterus (adenomyosis, fibroids)
• Fallopian tube (hydrosalpinx)
• Ovaries (ovarian cysts)
• Bladder (interstitial cystitis)
• Bowel (irritable bowel syndrome)
• Musculoskeletal system (piriformis syndrome).
Before pelvic pain is attributed to endometriosis, he says, the provider should rule out bowel, bladder, musculoskeletal, and psychiatric causes.

This article focuses on seven questions, the answers to which are critical to narrowing in on the diagnosis of endometriosis, including essential factors to consider in the patient history, imaging and other diagnostic tools, and considerations in surgical exploration.

1. WHY SUCH A LONG DELAY IN DIAGNOSIS?
Investigators exploring the length of time from a patient’s presentation with symptoms to diagnosis have found it to be particularly long for endometriosis, ranging from six to 11 years.

Because endometriosis is usually not high on the list of differential diagnoses for chronic pelvic pain in the primary care setting, a patient may not be referred to a gynecologist unless those symptoms include severe dysmenorrhea, dyspareunia, or similar findings. Once the referral is made, the gynecologist “will usually try contraceptive steroids, NSAIDs, or second-line progestins before a diagnosis is made,” says Dr. Giudice.⁵

The delay in diagnosis “is astounding,” she adds, “and has its roots in empiric medical therapies and a combination of patients fearing a diagnosis of cancer and reluctance of gynecologists to perform laparoscopy on adolescents.”⁶ Another possible cause of diagnostic delay: Some adolescent girls may not realize when their pain is severe. Because they may have always experienced a high degree of pain since menarche, they may assume it to be a normal aspect of womanhood and delay seeking help, says Pamela Stratton, MD.

Continue to learn any biomarkers proved to be useful diagnostic tools >>

2. HAVE ANY BIOMARKERS PROVED TO BE USEFUL DIAGNOSTIC TOOLS? 
Any biomarker proven to reliably identify endometriosis would be a boon to medicine, as it would provide a noninvasive or minimally invasive alternative to diagnostic laparoscopy, the current gold standard. Regrettably, the search for such a biomarker has produced “disappointing results,” says Dr. Giudice.

“Recent systematic reviews of all proposed endometriosis-related biomarkers over the past 25 years in serum, plasma, urine, and endometrium could not identify an unequivocally clinically useful biomarker or panel of biomarkers,” she notes.^7,8 “This is due mainly to low numbers of subjects, small populations for validations, cycle/hormonal- and disease stage–dependence, poorly defined controls, and low sensitivity and specificity.”

One hopeful development: “Whole genome transcriptomics of archived endometrial tissue and machine learning found several classifiers to diagnose and stage endometriosis with high accuracy that were validated on an independent sample set,” says Dr. Giudice.9 “However, these data now warrant a prospective, multisite study for further validation.”

Continue for key aspects of patient history >>

3. WHAT ASPECTS OF THE PATIENT HISTORY ARE KEY?
Dr. Stratton recommends that clinicians begin their evaluation of the patient with pain by asking her to describe that pain: how long she has had it, when it occurs, and which areas are affected.

“Most women with endometriosis-associated pain have chronic pelvic pain,” Dr. Stratton continues.⁵ “Up to 90% of those have dysmenorrhea or cyclic pain with menses.”¹⁰ In addition, women with endometriosis “commonly report having pain with any bleeding or spotting. About 30% of women diagnosed with endometriosis initially present to their gynecologist with dyspareunia.”¹¹

“Episodic pain with menses may become more constant, lasting for many days of the month,” says Dr. Stratton. “Women with dyschezia or dysuria may have endometriosis lesions associated with the bowel or bladder, respectively.¹² When women with these symptoms do not have lesions on the bowel or bladder, these pain symptoms may occur because of higher peritoneal hormone and inflammatory factor levels or because adjacent organs share the neural networks.”

Dr. Giudice views the history similarly: “I believe listening to the patient is essential in evaluating the possibility of her having endometriosis. This involves asking her to describe where her pain is, grading it on a scale of 1 to 10, identifying when in her cycle it occurs, and learning what makes it better or worse.”

“It also is important to assess the quality of the pain,” she adds. “Does it radiate, does it limit her daily activities, does it interfere with her relationships, intercourse, work, school? Is it associated with bowel movements, urination, other pain syndromes?”

“Having a pain questionnaire is a great help so that patients have a chance to reflect on these and other questions that help to frame the pain associated with endometriosis when they come for consultation,” she adds.

By determining if pain is associated with menstruation or spotting, the clinician is better informed about the value of menstrual suppression, says Dr. Stratton. “Determining what makes the pain better or worse can help define triggers which, if treated, can decrease the likelihood of episodes of pain.”

“A detailed history of any medical or surgical treatments and their outcome is helpful in guiding future treatment,” she adds. “While hormonal therapy has been a mainstay of treatment, in some women, some hormonal treatments may worsen pain or have unacceptable adverse effects, such as worsening depression or anxiety. In addition, some pain—especially that associated with deep lesions—may be relieved by surgical treatment;^13,14 pain that worsened after surgery may suggest neural damage.”

“As there is an engagement of the central nervous system, endometriosis is considered a central sensitivity syndrome in which women may also have other sites of pain,” Dr. Stratton says. “Thus, obtaining a history about current symptoms or prior diagnosis of irritable bowel syndrome, interstitial cystitis/painful bladder, migraines, fibromyalgia, or chronic fatigue syndrome is beneficial.^10,15-17 Facilitating treatment for these comorbidities is a key principle in helping women with endometriosis-associated pain, as any condition that triggers or perpetuates pain warrants treatment.”

Continue for what the physical exam entails >>

4. WHAT SHOULD THE PHYSICAL EXAM ENTAIL?
“An abdominal exam and a pelvic exam are essential in evaluating pain in a ­woman when endometriosis is suspected,” says Dr. Giudice. “Sometimes the latter is challenging in young teens and can be deferred.” Overall, however, “the pelvic exam can give insight into pain triggers, adnexal masses (possible endometriomas), and mobility of pelvic organs. A rectovaginal exam is important in evaluating deep infiltrating disease and to gauge the pelvic pain landscape overall. In addition, palpating the pelvic floor musculature is important to distinguish pelvic floor muscle spasm from endometriosis pain.”

“The challenge for clinicians is to think beyond the endometrial implants, taking into account multiple factors that influence pain perception,” says Dr. Stratton. During the examination, the clinician should begin by mapping the regions of pain in the abdomen and back, “distinguishing musculoskeletal pain from deep pain. Determining whether pains are focused or diffuse is also important.”

Dr. Stratton recommends that the routine pelvic exam be modified because a standard bimanual exam “confuses pain signals from the pelvic floor, abdominal wall, bladder, and other viscera. For this reason, a pain-oriented assessment is mandatory.”

Begin with a single digital examination to map tender areas, Dr. Stratton advises. Then consider the size, shape, and mobility of reproductive and pelvic organs. “A bimanual exam will help identify adnexal masses like endometriomas,” she says.

Endometriomas usually are not associated with pain, she adds, but “they are associated with deep infiltrating lesions. Nodularity along the uterosacral ligaments, limited reproductive organ mobility, and thickening of the rectovaginal septum also suggest deep infiltrating lesions. Importantly, deep infiltrating lesions are the lesion type most associated with pain.”^18,19

Continue to learn if imaging is useful in the diagnosis of endometriosis >>

5. IS IMAGING USEFUL IN THE DIAGNOSIS OF ENDOMETRIOSIS?
Laparoscopy remains the gold standard for diagnosis of endometriosis, observes Steven R. Goldstein, MD. Visualization of ­endometriotic implants at the time of surgery—with histologic assessment—offers definitive confirmation of the diagnosis. The physical examination, too, can offer a strong suggestion of endometriosis, he says.

“In the past, the pelvic examination and history often were the sine qua non for patients with pain,” Dr. Goldstein says. “Extreme dysmenorrhea and pain between periods, especially with intercourse, defecation, and exercise, all increased the suspicion of endometriosis. People used to talk about feeling nodularity in the uterosacral ligaments and finding decreased mobility of pelvic structures—but I don’t have any question that the skill of today’s gynecologists in doing a bimanual pelvic exam is a fraction of what it was in years gone by, because they haven’t had the necessity of experience. The first thing they do if there’s any question is send the patient for an ultrasound.”

Of course, ultrasound can be especially helpful in identifying endometriomas—sometimes called chocolate cysts—in the ovary. Endometriomas can have a solid appearance on ultrasound, says Dr. Goldstein, because the fluid they contain (dried blood) is sonolucent or pure black on ultrasound, similar to amniotic fluid or the fluid seen in the bladder. “This ‘chocolate’ fluid contained in endometriomas is homogeneous, particulate, and very monotonous in its appearance, in contrast to the internal echoes observed in hemorrhagic corpus lutea, which are very cobweb-like and can sometimes mimic papillary projections,” he adds.

“What’s absolutely essential when imaging a suspected endometrioma by ultrasound is that there be no evidence of any blood flow contained within that structure. Because it’s dried blood, it shouldn’t have any vascularity. If you see blood flow inside what you would call an endometrioma, you need to rethink your diagnosis,” he says.

In some cases, a supposed endometrioma lacks a black, sonolucent appearance, but “the clinician often can tell that it’s a cystic structure by the very bright posterior wall—what we call posterior wall acoustic enhancement—even though the interior of the structure may appear sort of grayish or whitish rather than the pure black of a simple cyst. It’s still fluid-filled,” Dr. Goldstein says.

In some instances, even endometriotic nodules can be imaged by ultrasound, he adds. “There’s an increasing body of literature that suggests that, if you look carefully in people with deep infiltrating endometriosis, you can often see solid-appearing nodules in the rectovaginal septum or between the uterus and bladder. With the kind of resolution that we now have with the vaginal probe, some of these nodules can be seen. That’s somewhat new, and it’s a function of two things—people looking for endometriosis and the better resolution of more modern equipment.”

Dr. Goldstein believes that MRI is “almost never” indicated in the diagnosis of endometriosis. A more helpful approach would be a consultative ultrasound with someone with more experience. However, when that is not available, or “in areas where you have excellent backup in terms of pelvic MRI, that may be the way to go. I don’t think so,” he demurs, “and some of my colleagues would be very upset at the thought of needing to use MRI to diagnose endometriosis. But in the occasional confusing or difficult case, depending on the quality of the referral pattern you have, it might make sense."

Continue to learn when diagnostic laparoscopy is clearly indicated >>

6. WHEN IS DIAGNOSTIC LAPAROSCOPY CLEARLY INDICATED?
Dr. Giudice believes that laparoscopy—with the intention to treat endometriosis, if present—“is essential when firstline medical therapy fails or when pain is acute and severe.”⁵

Dr. Stratton concurs. “Any woman with chronic pain wants to know what is causing the pain,” she says. Therefore, “women report a benefit from knowing that their pain is ­associated with endometriosis.6 However, diagnostic laparoscopy alone, with the sole purpose of determining the presence of endometriosis but not treating the lesions, is no longer performed, as it poses little benefit to the patient other than peace of mind.”

“The general trend in the US has been to first use hormonal treatments when the diagnosis of endometriosis is suspected, prior to performing surgery,” Dr. Stratton says.¹ In many cases, by using cyclic combined hormonal contraceptives to reduce menstrual flow or “suppressing menstruation with continuous combined hormonal contraceptives,” gonadotropin-releasing hormone analogues (combined with progestin to prevent bone loss) “or continuous progestin alone may be effective in decreasing pain. Not surprisingly, these hormonal approaches are effective for any chronic pelvic pain, even for women who do not have the surgical diagnosis of endometriosis.”²⁰

“When the firstline approach to chronic pelvic pain is hormonal treatment, laparoscopy is considered when these medical treatments have failed to control the pain or are poorly tolerated, or when the diagnosis of endometriosis is in question,” Dr. Stratton says.

“Laparoscopy to treat endometriomas is indicated if an endometrioma is enlarging or measures more than 4 cm in diameter, or if the diagnosis of an ovarian mass is in question,” she explains. “While surgeons have previously been aggressive in removing endometriomas, this practice may have negative consequences on ovarian function. Because endometriomas are pseudocysts, removing them completely leads to the removal of viable ovarian tissue and may diminish ovarian reserve.”^21,22

Continue for the surgical appearance of endometriosis >>

7. WHAT IS THE SURGICAL APPEARANCE OF ENDOMETRIOSIS?
Dr. Giudice returns to the enigmatic nature of endometriosis in addressing this question, mentioning its “many faces” at the time of surgery. “It is imperative that the surgeon recognize the disease in its many forms,” she says. “Also, it is especially helpful at the time of surgery if suspected lesions are biopsied and sent to pathology to have the diagnosis made unequivocally.”⁵

As for the surgical appearance of endometriosis, Dr. Stratton notes that there are three types of lesions—“superficial lesions, deep infiltrating lesions, and endometriomas. Endometriomas occur almost exclusively in the ovary and are pseudocysts without an identifiable cystic lining. They vary in dimension from a few millimeters to several centimeters.”

“Superficial peritoneal endometriosis lesions have a variable appearance, with some lesions being clear or red; some brown, blue or black; and some having a white appearance, like a scar,” says Dr. Stratton. “Endometriosis can be diagnosed on histologic examination of any of these lesion types."

“Overall, single-color lesions have similar frequencies of biopsy-confirmed endometriosis (59% to 62%),” she says.²³ “These lesion appearances likely represent different stages of development of endometriosis, with red or clear lesions occurring first, soon after endometrial tissue implantation; black, blue, or brown lesions occurring later, in response to the hormones varying in the menstrual cycle; and white lesions occurring as the lesions age. Deep infiltrating lesions generally have blue/black or white features.”

“Wide, deep, multiple-color lesions in the cul-de-sac, ovarian fossa, or uterosacral ligaments are most likely endometriosis,” Dr. Stratton adds.²³ Only lesions with multiple colors have a significantly higher percentage of positive biopsies (76%). Importantly, more than half of women with only subtle lesions (small red or white lesions) have endometriosis.

You tell the patient that endometriosis is one of the possible diagnoses for her chronic pelvic pain, and you take a focused history. During a pelvic examination, you observe that her right ovary lacks mobility, and you map a number of trigger points for her pain. Transvaginal ultrasound results suggest the presence of nodules in the rectovaginal septum. You begin empiric treatment with continuous combined hormonal contraceptives to suppress menstruation. On her next visit, M.L. reports reduced but still bothersome pain. Laparoscopy reveals a 2-cm endometrioma in the right ovary and deep infiltrating lesions in the cul-de-sac. The endometrioma is resected. Histology confirms the diagnosis of endometriosis. 

REFERENCES
1. American College of Obstetricians and Gynecologists. Practice Bulletin #114: Management of endometriosis. Obstet Gynecol. 2010; 116(1):223-236.
2. Sanfilippo JS, Wakim NG, Schikler KN, Yussman MA. Endometriosis in association with uterine anomaly. Am J Obstet Gynecol. 1986; 154(1):39-43.
3. Taylor HS, Bagot C, Kardana A. HOX gene expression is altered in the endometrium of women with endometriosis. Hum Reprod. 1999; 14(5):1328-1331.
4. Berkley KJ, Stratton P. Mechanisms: lessons from translational studies of endometriosis. In: Giamberardino MA, ed. Visceral Pain: Clinical, Pathophysiological and Therapeutic Aspects. Oxford, UK: Oxford University Press; 2009:39-50.
5. Giudice LC. Clinical practice: endometriosis. N Engl J Med. 2010;362(25): 2389-2398.
6. Ballard K, Lowton K, Wright J. What’s the delay: a qualitative study of women’s experiences of reaching a diagnosis of endometriosis. Fertil Steril. 2006;86(5):1296-1301.
7. May KE, Conduit-Hulbert SA, Villar J, et al. Peripheral biomarkers of endometriosis: a systematic review. Hum Reprod Update. 2010; 16(6):651-674.
8. May KE, Villar J, Kirtley S, et al. Endometrial alterations in endometriosis: a systematic review of putative biomarkers. Hum Reprod Update. 2011; 17(5):637-653.
9. Tamaresis JS, Irwin JC, Goldfien GA, et al. Molecular classification of endometriosis and disease stage using high-dimensional genomic data. Endocrinology. 2014;155(12):4986-4999.
10. Sinaii N, Cleary SD, Ballweg ML, et al. High rates of autoimmune and endocrine disorders, fibromyalgia, chronic fatigue syndrome and atopic diseases among women with endometriosis: a survey analysis. Hum Reprod. 2002;17(10):2715-2724.
11. De Graaff AA, D’Hooghe TM, Dunselman GA, et al. The significant effect of endometriosis on physical, mental and social wellbeing: results from an international cross-sectional survey. Hum Reprod. 2013;28(10):2677-2685.
12. Lafay Pillet MC, Huchon C, Santulli P, et al. A clinical score can predict associated deep infiltrating endometriosis before surgery for an endometrioma. Hum Reprod. 2014;29(8):1666-1676.
13. Healey M, Cheng C, Kaur H. To excise or ablate endometriosis? A prospective randomized double-blinded trial after 5-year follow-up. J Minim Invasive Gynecol. 2014;21(6):999-1004.
14. Anaf V, El Nakadi I, De Moor V, et al. Increased nerve density in deep infiltrating endometriotic nodules. Gynecol Obstet Invest. 2011;71(2):112-117.
15. Stratton P, Berkley KJ. Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications. Hum Reprod Update. 2011;17(3):327-346.
16. Karp BI, Sinaii N, Nieman LK, et al. Migraine in women with chronic pelvic pain with and without endometriosis. Fertil Steril. 2011;95(3):895-899.
17. Berkley KJ. A life of pelvic pain. Physiol Behav. 2005;86(3):272-280.
18. Fauconnier A, Chapron C. Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications. Hum Reprod Update. 2005;11(6):595-606.
19. Vercellini P, Fedele L, Aimi G, et al. Association between endometriosis stage, lesion type, patient characteristics and severity of pelvic pain symptoms: a multivariate analysis of over 1000 patients. Hum Reprod. 2007;22(1):266-271.
20. Ling FW. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Pelvic Pain Study Group. Obstet Gynecol. 1999;93(1):51-58.
21. Muzii L, Di Tucci C, Di Feliciantonio M, et al. The effect of surgery for endometrioma on ovarian reserve evaluated by antral follicle count: a systematic review and meta-analysis. Hum Reprod. 2014;29(10):2190-2198.
22. Muzii L, Luciano AA, Zupi E, Panici PB. Effect of surgery for endometrioma on ovarian function: a different point of view. J Minim Invasive Gynecol. 2014;21(4):531-533.
23. Stegmann BJ, Sinaii N, Liu S, et al. Using location, color, size, and depth to characterize and identify endometriosis lesions in a cohort of 133 women. Fertil Steril. 2008;89(6):1632-1636.

IN THIS ARTICLE
• The “why” of endometriosis
• Environmental factors, estrogen, and endometriosis
• Is imaging useful?
• When is diagnostic laparoscopy clearly indicated?

CASE M.L. is a 32-year-old nulliparous woman who is referred to your office by her primary care provider for chronic pelvic pain. She reports severe dysmenorrhea as her main symptom, but she also mentions dyspareunia. She says these symptoms have been present for several years but have increased in intensity gradually. She asks what you consider to be the most likely diagnosis.

What potential diagnoses do you mention to her? And how do you identify the cause of her pain?

Although endometriosis—the presence of endometrial tissue outside the uterus—affects at least 5 million women of reproductive age in the United States alone, it can be a challenging diagnosis for several reasons.

“Endometriosis is a great masquerader,” says Linda Giudice, MD, PhD. “It presents with a variety of pain patterns, intensities, and triggers. It can also involve symptoms that overlap those of other disorders, including disorders of the gastrointestinal and urinary tracts.”

Although endometriosis falls within the differential diagnosis of chronic pelvic pain, “it is usually not high on the list in the primary care setting (adult and adolescent),” adds Dr. Giudice.

John R. Lue, MD, MPH, an author of the most recent practice bulletin on endometriosis from the American College of Obstetricians and Gynecologists,¹ sees the situation similarly.

“The main challenge in the diagnosis of endometriosis is that its presentation mimics other causes of chronic pelvic pain,” he says. “Pelvic pain due to endometriosis is usually chronic (lasting ≥ 6 months). It is associated with dysmenorrhea in 50% to 90% of cases, as well as with dyspareunia, deep pelvic pain, and lower abdominal pain with or without back and loin pain. The pain can occur unpredictably and intermittently throughout the menstrual cycle or it can be continuous. In addition, it can be dull, throbbing, or sharp and may be exacerbated by physical activity.^2,3 Up to 20% of women with endometriosis have concurrent pain conditions.”⁴

There are three types of endometriosis lesions—endometriomas, which affect the ovary; superficial lesions; and deep infiltrating endometriosis. Peritoneal lesions may vary widely in appearance. Some may be clear or red; others brown, blue, or black; and some may have a white, scar-like appearance. To identify this elusive disease, it is critical that the clinician be able to recognize its “many faces.”

Among other diseases of the female pelvis that have a relatively similar presentation, Dr. Lue adds, are pathologies of the
• Uterus (adenomyosis, fibroids)
• Fallopian tube (hydrosalpinx)
• Ovaries (ovarian cysts)
• Bladder (interstitial cystitis)
• Bowel (irritable bowel syndrome)
• Musculoskeletal system (piriformis syndrome).
Before pelvic pain is attributed to endometriosis, he says, the provider should rule out bowel, bladder, musculoskeletal, and psychiatric causes.

This article focuses on seven questions, the answers to which are critical to narrowing in on the diagnosis of endometriosis, including essential factors to consider in the patient history, imaging and other diagnostic tools, and considerations in surgical exploration.

1. WHY SUCH A LONG DELAY IN DIAGNOSIS?
Investigators exploring the length of time from a patient’s presentation with symptoms to diagnosis have found it to be particularly long for endometriosis, ranging from six to 11 years.

Because endometriosis is usually not high on the list of differential diagnoses for chronic pelvic pain in the primary care setting, a patient may not be referred to a gynecologist unless those symptoms include severe dysmenorrhea, dyspareunia, or similar findings. Once the referral is made, the gynecologist “will usually try contraceptive steroids, NSAIDs, or second-line progestins before a diagnosis is made,” says Dr. Giudice.⁵

The delay in diagnosis “is astounding,” she adds, “and has its roots in empiric medical therapies and a combination of patients fearing a diagnosis of cancer and reluctance of gynecologists to perform laparoscopy on adolescents.”⁶ Another possible cause of diagnostic delay: Some adolescent girls may not realize when their pain is severe. Because they may have always experienced a high degree of pain since menarche, they may assume it to be a normal aspect of womanhood and delay seeking help, says Pamela Stratton, MD.

Continue to learn any biomarkers proved to be useful diagnostic tools >>

2. HAVE ANY BIOMARKERS PROVED TO BE USEFUL DIAGNOSTIC TOOLS? 
Any biomarker proven to reliably identify endometriosis would be a boon to medicine, as it would provide a noninvasive or minimally invasive alternative to diagnostic laparoscopy, the current gold standard. Regrettably, the search for such a biomarker has produced “disappointing results,” says Dr. Giudice.

“Recent systematic reviews of all proposed endometriosis-related biomarkers over the past 25 years in serum, plasma, urine, and endometrium could not identify an unequivocally clinically useful biomarker or panel of biomarkers,” she notes.^7,8 “This is due mainly to low numbers of subjects, small populations for validations, cycle/hormonal- and disease stage–dependence, poorly defined controls, and low sensitivity and specificity.”

One hopeful development: “Whole genome transcriptomics of archived endometrial tissue and machine learning found several classifiers to diagnose and stage endometriosis with high accuracy that were validated on an independent sample set,” says Dr. Giudice.9 “However, these data now warrant a prospective, multisite study for further validation.”

Continue for key aspects of patient history >>

3. WHAT ASPECTS OF THE PATIENT HISTORY ARE KEY?
Dr. Stratton recommends that clinicians begin their evaluation of the patient with pain by asking her to describe that pain: how long she has had it, when it occurs, and which areas are affected.

“Most women with endometriosis-associated pain have chronic pelvic pain,” Dr. Stratton continues.⁵ “Up to 90% of those have dysmenorrhea or cyclic pain with menses.”¹⁰ In addition, women with endometriosis “commonly report having pain with any bleeding or spotting. About 30% of women diagnosed with endometriosis initially present to their gynecologist with dyspareunia.”¹¹

“Episodic pain with menses may become more constant, lasting for many days of the month,” says Dr. Stratton. “Women with dyschezia or dysuria may have endometriosis lesions associated with the bowel or bladder, respectively.¹² When women with these symptoms do not have lesions on the bowel or bladder, these pain symptoms may occur because of higher peritoneal hormone and inflammatory factor levels or because adjacent organs share the neural networks.”

Dr. Giudice views the history similarly: “I believe listening to the patient is essential in evaluating the possibility of her having endometriosis. This involves asking her to describe where her pain is, grading it on a scale of 1 to 10, identifying when in her cycle it occurs, and learning what makes it better or worse.”

“It also is important to assess the quality of the pain,” she adds. “Does it radiate, does it limit her daily activities, does it interfere with her relationships, intercourse, work, school? Is it associated with bowel movements, urination, other pain syndromes?”

“Having a pain questionnaire is a great help so that patients have a chance to reflect on these and other questions that help to frame the pain associated with endometriosis when they come for consultation,” she adds.

By determining if pain is associated with menstruation or spotting, the clinician is better informed about the value of menstrual suppression, says Dr. Stratton. “Determining what makes the pain better or worse can help define triggers which, if treated, can decrease the likelihood of episodes of pain.”

“A detailed history of any medical or surgical treatments and their outcome is helpful in guiding future treatment,” she adds. “While hormonal therapy has been a mainstay of treatment, in some women, some hormonal treatments may worsen pain or have unacceptable adverse effects, such as worsening depression or anxiety. In addition, some pain—especially that associated with deep lesions—may be relieved by surgical treatment;^13,14 pain that worsened after surgery may suggest neural damage.”

“As there is an engagement of the central nervous system, endometriosis is considered a central sensitivity syndrome in which women may also have other sites of pain,” Dr. Stratton says. “Thus, obtaining a history about current symptoms or prior diagnosis of irritable bowel syndrome, interstitial cystitis/painful bladder, migraines, fibromyalgia, or chronic fatigue syndrome is beneficial.^10,15-17 Facilitating treatment for these comorbidities is a key principle in helping women with endometriosis-associated pain, as any condition that triggers or perpetuates pain warrants treatment.”

Continue for what the physical exam entails >>

4. WHAT SHOULD THE PHYSICAL EXAM ENTAIL?
“An abdominal exam and a pelvic exam are essential in evaluating pain in a ­woman when endometriosis is suspected,” says Dr. Giudice. “Sometimes the latter is challenging in young teens and can be deferred.” Overall, however, “the pelvic exam can give insight into pain triggers, adnexal masses (possible endometriomas), and mobility of pelvic organs. A rectovaginal exam is important in evaluating deep infiltrating disease and to gauge the pelvic pain landscape overall. In addition, palpating the pelvic floor musculature is important to distinguish pelvic floor muscle spasm from endometriosis pain.”

“The challenge for clinicians is to think beyond the endometrial implants, taking into account multiple factors that influence pain perception,” says Dr. Stratton. During the examination, the clinician should begin by mapping the regions of pain in the abdomen and back, “distinguishing musculoskeletal pain from deep pain. Determining whether pains are focused or diffuse is also important.”

Dr. Stratton recommends that the routine pelvic exam be modified because a standard bimanual exam “confuses pain signals from the pelvic floor, abdominal wall, bladder, and other viscera. For this reason, a pain-oriented assessment is mandatory.”

Begin with a single digital examination to map tender areas, Dr. Stratton advises. Then consider the size, shape, and mobility of reproductive and pelvic organs. “A bimanual exam will help identify adnexal masses like endometriomas,” she says.

Endometriomas usually are not associated with pain, she adds, but “they are associated with deep infiltrating lesions. Nodularity along the uterosacral ligaments, limited reproductive organ mobility, and thickening of the rectovaginal septum also suggest deep infiltrating lesions. Importantly, deep infiltrating lesions are the lesion type most associated with pain.”^18,19

Continue to learn if imaging is useful in the diagnosis of endometriosis >>

5. IS IMAGING USEFUL IN THE DIAGNOSIS OF ENDOMETRIOSIS?
Laparoscopy remains the gold standard for diagnosis of endometriosis, observes Steven R. Goldstein, MD. Visualization of ­endometriotic implants at the time of surgery—with histologic assessment—offers definitive confirmation of the diagnosis. The physical examination, too, can offer a strong suggestion of endometriosis, he says.

“In the past, the pelvic examination and history often were the sine qua non for patients with pain,” Dr. Goldstein says. “Extreme dysmenorrhea and pain between periods, especially with intercourse, defecation, and exercise, all increased the suspicion of endometriosis. People used to talk about feeling nodularity in the uterosacral ligaments and finding decreased mobility of pelvic structures—but I don’t have any question that the skill of today’s gynecologists in doing a bimanual pelvic exam is a fraction of what it was in years gone by, because they haven’t had the necessity of experience. The first thing they do if there’s any question is send the patient for an ultrasound.”

Of course, ultrasound can be especially helpful in identifying endometriomas—sometimes called chocolate cysts—in the ovary. Endometriomas can have a solid appearance on ultrasound, says Dr. Goldstein, because the fluid they contain (dried blood) is sonolucent or pure black on ultrasound, similar to amniotic fluid or the fluid seen in the bladder. “This ‘chocolate’ fluid contained in endometriomas is homogeneous, particulate, and very monotonous in its appearance, in contrast to the internal echoes observed in hemorrhagic corpus lutea, which are very cobweb-like and can sometimes mimic papillary projections,” he adds.

“What’s absolutely essential when imaging a suspected endometrioma by ultrasound is that there be no evidence of any blood flow contained within that structure. Because it’s dried blood, it shouldn’t have any vascularity. If you see blood flow inside what you would call an endometrioma, you need to rethink your diagnosis,” he says.

In some cases, a supposed endometrioma lacks a black, sonolucent appearance, but “the clinician often can tell that it’s a cystic structure by the very bright posterior wall—what we call posterior wall acoustic enhancement—even though the interior of the structure may appear sort of grayish or whitish rather than the pure black of a simple cyst. It’s still fluid-filled,” Dr. Goldstein says.

In some instances, even endometriotic nodules can be imaged by ultrasound, he adds. “There’s an increasing body of literature that suggests that, if you look carefully in people with deep infiltrating endometriosis, you can often see solid-appearing nodules in the rectovaginal septum or between the uterus and bladder. With the kind of resolution that we now have with the vaginal probe, some of these nodules can be seen. That’s somewhat new, and it’s a function of two things—people looking for endometriosis and the better resolution of more modern equipment.”

Dr. Goldstein believes that MRI is “almost never” indicated in the diagnosis of endometriosis. A more helpful approach would be a consultative ultrasound with someone with more experience. However, when that is not available, or “in areas where you have excellent backup in terms of pelvic MRI, that may be the way to go. I don’t think so,” he demurs, “and some of my colleagues would be very upset at the thought of needing to use MRI to diagnose endometriosis. But in the occasional confusing or difficult case, depending on the quality of the referral pattern you have, it might make sense."

Continue to learn when diagnostic laparoscopy is clearly indicated >>

6. WHEN IS DIAGNOSTIC LAPAROSCOPY CLEARLY INDICATED?
Dr. Giudice believes that laparoscopy—with the intention to treat endometriosis, if present—“is essential when firstline medical therapy fails or when pain is acute and severe.”⁵

Dr. Stratton concurs. “Any woman with chronic pain wants to know what is causing the pain,” she says. Therefore, “women report a benefit from knowing that their pain is ­associated with endometriosis.6 However, diagnostic laparoscopy alone, with the sole purpose of determining the presence of endometriosis but not treating the lesions, is no longer performed, as it poses little benefit to the patient other than peace of mind.”

“The general trend in the US has been to first use hormonal treatments when the diagnosis of endometriosis is suspected, prior to performing surgery,” Dr. Stratton says.¹ In many cases, by using cyclic combined hormonal contraceptives to reduce menstrual flow or “suppressing menstruation with continuous combined hormonal contraceptives,” gonadotropin-releasing hormone analogues (combined with progestin to prevent bone loss) “or continuous progestin alone may be effective in decreasing pain. Not surprisingly, these hormonal approaches are effective for any chronic pelvic pain, even for women who do not have the surgical diagnosis of endometriosis.”²⁰

“When the firstline approach to chronic pelvic pain is hormonal treatment, laparoscopy is considered when these medical treatments have failed to control the pain or are poorly tolerated, or when the diagnosis of endometriosis is in question,” Dr. Stratton says.

“Laparoscopy to treat endometriomas is indicated if an endometrioma is enlarging or measures more than 4 cm in diameter, or if the diagnosis of an ovarian mass is in question,” she explains. “While surgeons have previously been aggressive in removing endometriomas, this practice may have negative consequences on ovarian function. Because endometriomas are pseudocysts, removing them completely leads to the removal of viable ovarian tissue and may diminish ovarian reserve.”^21,22

Continue for the surgical appearance of endometriosis >>

7. WHAT IS THE SURGICAL APPEARANCE OF ENDOMETRIOSIS?
Dr. Giudice returns to the enigmatic nature of endometriosis in addressing this question, mentioning its “many faces” at the time of surgery. “It is imperative that the surgeon recognize the disease in its many forms,” she says. “Also, it is especially helpful at the time of surgery if suspected lesions are biopsied and sent to pathology to have the diagnosis made unequivocally.”⁵

As for the surgical appearance of endometriosis, Dr. Stratton notes that there are three types of lesions—“superficial lesions, deep infiltrating lesions, and endometriomas. Endometriomas occur almost exclusively in the ovary and are pseudocysts without an identifiable cystic lining. They vary in dimension from a few millimeters to several centimeters.”

“Superficial peritoneal endometriosis lesions have a variable appearance, with some lesions being clear or red; some brown, blue or black; and some having a white appearance, like a scar,” says Dr. Stratton. “Endometriosis can be diagnosed on histologic examination of any of these lesion types."

“Overall, single-color lesions have similar frequencies of biopsy-confirmed endometriosis (59% to 62%),” she says.²³ “These lesion appearances likely represent different stages of development of endometriosis, with red or clear lesions occurring first, soon after endometrial tissue implantation; black, blue, or brown lesions occurring later, in response to the hormones varying in the menstrual cycle; and white lesions occurring as the lesions age. Deep infiltrating lesions generally have blue/black or white features.”

“Wide, deep, multiple-color lesions in the cul-de-sac, ovarian fossa, or uterosacral ligaments are most likely endometriosis,” Dr. Stratton adds.²³ Only lesions with multiple colors have a significantly higher percentage of positive biopsies (76%). Importantly, more than half of women with only subtle lesions (small red or white lesions) have endometriosis.

You tell the patient that endometriosis is one of the possible diagnoses for her chronic pelvic pain, and you take a focused history. During a pelvic examination, you observe that her right ovary lacks mobility, and you map a number of trigger points for her pain. Transvaginal ultrasound results suggest the presence of nodules in the rectovaginal septum. You begin empiric treatment with continuous combined hormonal contraceptives to suppress menstruation. On her next visit, M.L. reports reduced but still bothersome pain. Laparoscopy reveals a 2-cm endometrioma in the right ovary and deep infiltrating lesions in the cul-de-sac. The endometrioma is resected. Histology confirms the diagnosis of endometriosis. 

REFERENCES
1. American College of Obstetricians and Gynecologists. Practice Bulletin #114: Management of endometriosis. Obstet Gynecol. 2010; 116(1):223-236.
2. Sanfilippo JS, Wakim NG, Schikler KN, Yussman MA. Endometriosis in association with uterine anomaly. Am J Obstet Gynecol. 1986; 154(1):39-43.
3. Taylor HS, Bagot C, Kardana A. HOX gene expression is altered in the endometrium of women with endometriosis. Hum Reprod. 1999; 14(5):1328-1331.
4. Berkley KJ, Stratton P. Mechanisms: lessons from translational studies of endometriosis. In: Giamberardino MA, ed. Visceral Pain: Clinical, Pathophysiological and Therapeutic Aspects. Oxford, UK: Oxford University Press; 2009:39-50.
5. Giudice LC. Clinical practice: endometriosis. N Engl J Med. 2010;362(25): 2389-2398.
6. Ballard K, Lowton K, Wright J. What’s the delay: a qualitative study of women’s experiences of reaching a diagnosis of endometriosis. Fertil Steril. 2006;86(5):1296-1301.
7. May KE, Conduit-Hulbert SA, Villar J, et al. Peripheral biomarkers of endometriosis: a systematic review. Hum Reprod Update. 2010; 16(6):651-674.
8. May KE, Villar J, Kirtley S, et al. Endometrial alterations in endometriosis: a systematic review of putative biomarkers. Hum Reprod Update. 2011; 17(5):637-653.
9. Tamaresis JS, Irwin JC, Goldfien GA, et al. Molecular classification of endometriosis and disease stage using high-dimensional genomic data. Endocrinology. 2014;155(12):4986-4999.
10. Sinaii N, Cleary SD, Ballweg ML, et al. High rates of autoimmune and endocrine disorders, fibromyalgia, chronic fatigue syndrome and atopic diseases among women with endometriosis: a survey analysis. Hum Reprod. 2002;17(10):2715-2724.
11. De Graaff AA, D’Hooghe TM, Dunselman GA, et al. The significant effect of endometriosis on physical, mental and social wellbeing: results from an international cross-sectional survey. Hum Reprod. 2013;28(10):2677-2685.
12. Lafay Pillet MC, Huchon C, Santulli P, et al. A clinical score can predict associated deep infiltrating endometriosis before surgery for an endometrioma. Hum Reprod. 2014;29(8):1666-1676.
13. Healey M, Cheng C, Kaur H. To excise or ablate endometriosis? A prospective randomized double-blinded trial after 5-year follow-up. J Minim Invasive Gynecol. 2014;21(6):999-1004.
14. Anaf V, El Nakadi I, De Moor V, et al. Increased nerve density in deep infiltrating endometriotic nodules. Gynecol Obstet Invest. 2011;71(2):112-117.
15. Stratton P, Berkley KJ. Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications. Hum Reprod Update. 2011;17(3):327-346.
16. Karp BI, Sinaii N, Nieman LK, et al. Migraine in women with chronic pelvic pain with and without endometriosis. Fertil Steril. 2011;95(3):895-899.
17. Berkley KJ. A life of pelvic pain. Physiol Behav. 2005;86(3):272-280.
18. Fauconnier A, Chapron C. Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications. Hum Reprod Update. 2005;11(6):595-606.
19. Vercellini P, Fedele L, Aimi G, et al. Association between endometriosis stage, lesion type, patient characteristics and severity of pelvic pain symptoms: a multivariate analysis of over 1000 patients. Hum Reprod. 2007;22(1):266-271.
20. Ling FW. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Pelvic Pain Study Group. Obstet Gynecol. 1999;93(1):51-58.
21. Muzii L, Di Tucci C, Di Feliciantonio M, et al. The effect of surgery for endometrioma on ovarian reserve evaluated by antral follicle count: a systematic review and meta-analysis. Hum Reprod. 2014;29(10):2190-2198.
22. Muzii L, Luciano AA, Zupi E, Panici PB. Effect of surgery for endometrioma on ovarian function: a different point of view. J Minim Invasive Gynecol. 2014;21(4):531-533.
23. Stegmann BJ, Sinaii N, Liu S, et al. Using location, color, size, and depth to characterize and identify endometriosis lesions in a cohort of 133 women. Fertil Steril. 2008;89(6):1632-1636.

IN THIS ARTICLE
• The “why” of endometriosis
• Environmental factors, estrogen, and endometriosis
• Is imaging useful?
• When is diagnostic laparoscopy clearly indicated?

CASE M.L. is a 32-year-old nulliparous woman who is referred to your office by her primary care provider for chronic pelvic pain. She reports severe dysmenorrhea as her main symptom, but she also mentions dyspareunia. She says these symptoms have been present for several years but have increased in intensity gradually. She asks what you consider to be the most likely diagnosis.

What potential diagnoses do you mention to her? And how do you identify the cause of her pain?

Although endometriosis—the presence of endometrial tissue outside the uterus—affects at least 5 million women of reproductive age in the United States alone, it can be a challenging diagnosis for several reasons.

“Endometriosis is a great masquerader,” says Linda Giudice, MD, PhD. “It presents with a variety of pain patterns, intensities, and triggers. It can also involve symptoms that overlap those of other disorders, including disorders of the gastrointestinal and urinary tracts.”

Although endometriosis falls within the differential diagnosis of chronic pelvic pain, “it is usually not high on the list in the primary care setting (adult and adolescent),” adds Dr. Giudice.

John R. Lue, MD, MPH, an author of the most recent practice bulletin on endometriosis from the American College of Obstetricians and Gynecologists,¹ sees the situation similarly.

“The main challenge in the diagnosis of endometriosis is that its presentation mimics other causes of chronic pelvic pain,” he says. “Pelvic pain due to endometriosis is usually chronic (lasting ≥ 6 months). It is associated with dysmenorrhea in 50% to 90% of cases, as well as with dyspareunia, deep pelvic pain, and lower abdominal pain with or without back and loin pain. The pain can occur unpredictably and intermittently throughout the menstrual cycle or it can be continuous. In addition, it can be dull, throbbing, or sharp and may be exacerbated by physical activity.^2,3 Up to 20% of women with endometriosis have concurrent pain conditions.”⁴

There are three types of endometriosis lesions—endometriomas, which affect the ovary; superficial lesions; and deep infiltrating endometriosis. Peritoneal lesions may vary widely in appearance. Some may be clear or red; others brown, blue, or black; and some may have a white, scar-like appearance. To identify this elusive disease, it is critical that the clinician be able to recognize its “many faces.”

Among other diseases of the female pelvis that have a relatively similar presentation, Dr. Lue adds, are pathologies of the
• Uterus (adenomyosis, fibroids)
• Fallopian tube (hydrosalpinx)
• Ovaries (ovarian cysts)
• Bladder (interstitial cystitis)
• Bowel (irritable bowel syndrome)
• Musculoskeletal system (piriformis syndrome).
Before pelvic pain is attributed to endometriosis, he says, the provider should rule out bowel, bladder, musculoskeletal, and psychiatric causes.

This article focuses on seven questions, the answers to which are critical to narrowing in on the diagnosis of endometriosis, including essential factors to consider in the patient history, imaging and other diagnostic tools, and considerations in surgical exploration.

1. WHY SUCH A LONG DELAY IN DIAGNOSIS?
Investigators exploring the length of time from a patient’s presentation with symptoms to diagnosis have found it to be particularly long for endometriosis, ranging from six to 11 years.

Because endometriosis is usually not high on the list of differential diagnoses for chronic pelvic pain in the primary care setting, a patient may not be referred to a gynecologist unless those symptoms include severe dysmenorrhea, dyspareunia, or similar findings. Once the referral is made, the gynecologist “will usually try contraceptive steroids, NSAIDs, or second-line progestins before a diagnosis is made,” says Dr. Giudice.⁵

The delay in diagnosis “is astounding,” she adds, “and has its roots in empiric medical therapies and a combination of patients fearing a diagnosis of cancer and reluctance of gynecologists to perform laparoscopy on adolescents.”⁶ Another possible cause of diagnostic delay: Some adolescent girls may not realize when their pain is severe. Because they may have always experienced a high degree of pain since menarche, they may assume it to be a normal aspect of womanhood and delay seeking help, says Pamela Stratton, MD.

Continue to learn any biomarkers proved to be useful diagnostic tools >>

2. HAVE ANY BIOMARKERS PROVED TO BE USEFUL DIAGNOSTIC TOOLS? 
Any biomarker proven to reliably identify endometriosis would be a boon to medicine, as it would provide a noninvasive or minimally invasive alternative to diagnostic laparoscopy, the current gold standard. Regrettably, the search for such a biomarker has produced “disappointing results,” says Dr. Giudice.

“Recent systematic reviews of all proposed endometriosis-related biomarkers over the past 25 years in serum, plasma, urine, and endometrium could not identify an unequivocally clinically useful biomarker or panel of biomarkers,” she notes.^7,8 “This is due mainly to low numbers of subjects, small populations for validations, cycle/hormonal- and disease stage–dependence, poorly defined controls, and low sensitivity and specificity.”

One hopeful development: “Whole genome transcriptomics of archived endometrial tissue and machine learning found several classifiers to diagnose and stage endometriosis with high accuracy that were validated on an independent sample set,” says Dr. Giudice.9 “However, these data now warrant a prospective, multisite study for further validation.”

Continue for key aspects of patient history >>

3. WHAT ASPECTS OF THE PATIENT HISTORY ARE KEY?
Dr. Stratton recommends that clinicians begin their evaluation of the patient with pain by asking her to describe that pain: how long she has had it, when it occurs, and which areas are affected.

“Most women with endometriosis-associated pain have chronic pelvic pain,” Dr. Stratton continues.⁵ “Up to 90% of those have dysmenorrhea or cyclic pain with menses.”¹⁰ In addition, women with endometriosis “commonly report having pain with any bleeding or spotting. About 30% of women diagnosed with endometriosis initially present to their gynecologist with dyspareunia.”¹¹

“Episodic pain with menses may become more constant, lasting for many days of the month,” says Dr. Stratton. “Women with dyschezia or dysuria may have endometriosis lesions associated with the bowel or bladder, respectively.¹² When women with these symptoms do not have lesions on the bowel or bladder, these pain symptoms may occur because of higher peritoneal hormone and inflammatory factor levels or because adjacent organs share the neural networks.”

Dr. Giudice views the history similarly: “I believe listening to the patient is essential in evaluating the possibility of her having endometriosis. This involves asking her to describe where her pain is, grading it on a scale of 1 to 10, identifying when in her cycle it occurs, and learning what makes it better or worse.”

“It also is important to assess the quality of the pain,” she adds. “Does it radiate, does it limit her daily activities, does it interfere with her relationships, intercourse, work, school? Is it associated with bowel movements, urination, other pain syndromes?”

“Having a pain questionnaire is a great help so that patients have a chance to reflect on these and other questions that help to frame the pain associated with endometriosis when they come for consultation,” she adds.

By determining if pain is associated with menstruation or spotting, the clinician is better informed about the value of menstrual suppression, says Dr. Stratton. “Determining what makes the pain better or worse can help define triggers which, if treated, can decrease the likelihood of episodes of pain.”

“A detailed history of any medical or surgical treatments and their outcome is helpful in guiding future treatment,” she adds. “While hormonal therapy has been a mainstay of treatment, in some women, some hormonal treatments may worsen pain or have unacceptable adverse effects, such as worsening depression or anxiety. In addition, some pain—especially that associated with deep lesions—may be relieved by surgical treatment;^13,14 pain that worsened after surgery may suggest neural damage.”

“As there is an engagement of the central nervous system, endometriosis is considered a central sensitivity syndrome in which women may also have other sites of pain,” Dr. Stratton says. “Thus, obtaining a history about current symptoms or prior diagnosis of irritable bowel syndrome, interstitial cystitis/painful bladder, migraines, fibromyalgia, or chronic fatigue syndrome is beneficial.^10,15-17 Facilitating treatment for these comorbidities is a key principle in helping women with endometriosis-associated pain, as any condition that triggers or perpetuates pain warrants treatment.”

Continue for what the physical exam entails >>

4. WHAT SHOULD THE PHYSICAL EXAM ENTAIL?
“An abdominal exam and a pelvic exam are essential in evaluating pain in a ­woman when endometriosis is suspected,” says Dr. Giudice. “Sometimes the latter is challenging in young teens and can be deferred.” Overall, however, “the pelvic exam can give insight into pain triggers, adnexal masses (possible endometriomas), and mobility of pelvic organs. A rectovaginal exam is important in evaluating deep infiltrating disease and to gauge the pelvic pain landscape overall. In addition, palpating the pelvic floor musculature is important to distinguish pelvic floor muscle spasm from endometriosis pain.”

“The challenge for clinicians is to think beyond the endometrial implants, taking into account multiple factors that influence pain perception,” says Dr. Stratton. During the examination, the clinician should begin by mapping the regions of pain in the abdomen and back, “distinguishing musculoskeletal pain from deep pain. Determining whether pains are focused or diffuse is also important.”

Dr. Stratton recommends that the routine pelvic exam be modified because a standard bimanual exam “confuses pain signals from the pelvic floor, abdominal wall, bladder, and other viscera. For this reason, a pain-oriented assessment is mandatory.”

Begin with a single digital examination to map tender areas, Dr. Stratton advises. Then consider the size, shape, and mobility of reproductive and pelvic organs. “A bimanual exam will help identify adnexal masses like endometriomas,” she says.

Endometriomas usually are not associated with pain, she adds, but “they are associated with deep infiltrating lesions. Nodularity along the uterosacral ligaments, limited reproductive organ mobility, and thickening of the rectovaginal septum also suggest deep infiltrating lesions. Importantly, deep infiltrating lesions are the lesion type most associated with pain.”^18,19

Continue to learn if imaging is useful in the diagnosis of endometriosis >>

5. IS IMAGING USEFUL IN THE DIAGNOSIS OF ENDOMETRIOSIS?
Laparoscopy remains the gold standard for diagnosis of endometriosis, observes Steven R. Goldstein, MD. Visualization of ­endometriotic implants at the time of surgery—with histologic assessment—offers definitive confirmation of the diagnosis. The physical examination, too, can offer a strong suggestion of endometriosis, he says.

“In the past, the pelvic examination and history often were the sine qua non for patients with pain,” Dr. Goldstein says. “Extreme dysmenorrhea and pain between periods, especially with intercourse, defecation, and exercise, all increased the suspicion of endometriosis. People used to talk about feeling nodularity in the uterosacral ligaments and finding decreased mobility of pelvic structures—but I don’t have any question that the skill of today’s gynecologists in doing a bimanual pelvic exam is a fraction of what it was in years gone by, because they haven’t had the necessity of experience. The first thing they do if there’s any question is send the patient for an ultrasound.”

Of course, ultrasound can be especially helpful in identifying endometriomas—sometimes called chocolate cysts—in the ovary. Endometriomas can have a solid appearance on ultrasound, says Dr. Goldstein, because the fluid they contain (dried blood) is sonolucent or pure black on ultrasound, similar to amniotic fluid or the fluid seen in the bladder. “This ‘chocolate’ fluid contained in endometriomas is homogeneous, particulate, and very monotonous in its appearance, in contrast to the internal echoes observed in hemorrhagic corpus lutea, which are very cobweb-like and can sometimes mimic papillary projections,” he adds.

“What’s absolutely essential when imaging a suspected endometrioma by ultrasound is that there be no evidence of any blood flow contained within that structure. Because it’s dried blood, it shouldn’t have any vascularity. If you see blood flow inside what you would call an endometrioma, you need to rethink your diagnosis,” he says.

In some cases, a supposed endometrioma lacks a black, sonolucent appearance, but “the clinician often can tell that it’s a cystic structure by the very bright posterior wall—what we call posterior wall acoustic enhancement—even though the interior of the structure may appear sort of grayish or whitish rather than the pure black of a simple cyst. It’s still fluid-filled,” Dr. Goldstein says.

In some instances, even endometriotic nodules can be imaged by ultrasound, he adds. “There’s an increasing body of literature that suggests that, if you look carefully in people with deep infiltrating endometriosis, you can often see solid-appearing nodules in the rectovaginal septum or between the uterus and bladder. With the kind of resolution that we now have with the vaginal probe, some of these nodules can be seen. That’s somewhat new, and it’s a function of two things—people looking for endometriosis and the better resolution of more modern equipment.”

Dr. Goldstein believes that MRI is “almost never” indicated in the diagnosis of endometriosis. A more helpful approach would be a consultative ultrasound with someone with more experience. However, when that is not available, or “in areas where you have excellent backup in terms of pelvic MRI, that may be the way to go. I don’t think so,” he demurs, “and some of my colleagues would be very upset at the thought of needing to use MRI to diagnose endometriosis. But in the occasional confusing or difficult case, depending on the quality of the referral pattern you have, it might make sense."

Continue to learn when diagnostic laparoscopy is clearly indicated >>

6. WHEN IS DIAGNOSTIC LAPAROSCOPY CLEARLY INDICATED?
Dr. Giudice believes that laparoscopy—with the intention to treat endometriosis, if present—“is essential when firstline medical therapy fails or when pain is acute and severe.”⁵

Dr. Stratton concurs. “Any woman with chronic pain wants to know what is causing the pain,” she says. Therefore, “women report a benefit from knowing that their pain is ­associated with endometriosis.6 However, diagnostic laparoscopy alone, with the sole purpose of determining the presence of endometriosis but not treating the lesions, is no longer performed, as it poses little benefit to the patient other than peace of mind.”

“The general trend in the US has been to first use hormonal treatments when the diagnosis of endometriosis is suspected, prior to performing surgery,” Dr. Stratton says.¹ In many cases, by using cyclic combined hormonal contraceptives to reduce menstrual flow or “suppressing menstruation with continuous combined hormonal contraceptives,” gonadotropin-releasing hormone analogues (combined with progestin to prevent bone loss) “or continuous progestin alone may be effective in decreasing pain. Not surprisingly, these hormonal approaches are effective for any chronic pelvic pain, even for women who do not have the surgical diagnosis of endometriosis.”²⁰

“When the firstline approach to chronic pelvic pain is hormonal treatment, laparoscopy is considered when these medical treatments have failed to control the pain or are poorly tolerated, or when the diagnosis of endometriosis is in question,” Dr. Stratton says.

“Laparoscopy to treat endometriomas is indicated if an endometrioma is enlarging or measures more than 4 cm in diameter, or if the diagnosis of an ovarian mass is in question,” she explains. “While surgeons have previously been aggressive in removing endometriomas, this practice may have negative consequences on ovarian function. Because endometriomas are pseudocysts, removing them completely leads to the removal of viable ovarian tissue and may diminish ovarian reserve.”^21,22

Continue for the surgical appearance of endometriosis >>

7. WHAT IS THE SURGICAL APPEARANCE OF ENDOMETRIOSIS?
Dr. Giudice returns to the enigmatic nature of endometriosis in addressing this question, mentioning its “many faces” at the time of surgery. “It is imperative that the surgeon recognize the disease in its many forms,” she says. “Also, it is especially helpful at the time of surgery if suspected lesions are biopsied and sent to pathology to have the diagnosis made unequivocally.”⁵

As for the surgical appearance of endometriosis, Dr. Stratton notes that there are three types of lesions—“superficial lesions, deep infiltrating lesions, and endometriomas. Endometriomas occur almost exclusively in the ovary and are pseudocysts without an identifiable cystic lining. They vary in dimension from a few millimeters to several centimeters.”

“Superficial peritoneal endometriosis lesions have a variable appearance, with some lesions being clear or red; some brown, blue or black; and some having a white appearance, like a scar,” says Dr. Stratton. “Endometriosis can be diagnosed on histologic examination of any of these lesion types."

“Overall, single-color lesions have similar frequencies of biopsy-confirmed endometriosis (59% to 62%),” she says.²³ “These lesion appearances likely represent different stages of development of endometriosis, with red or clear lesions occurring first, soon after endometrial tissue implantation; black, blue, or brown lesions occurring later, in response to the hormones varying in the menstrual cycle; and white lesions occurring as the lesions age. Deep infiltrating lesions generally have blue/black or white features.”

“Wide, deep, multiple-color lesions in the cul-de-sac, ovarian fossa, or uterosacral ligaments are most likely endometriosis,” Dr. Stratton adds.²³ Only lesions with multiple colors have a significantly higher percentage of positive biopsies (76%). Importantly, more than half of women with only subtle lesions (small red or white lesions) have endometriosis.

You tell the patient that endometriosis is one of the possible diagnoses for her chronic pelvic pain, and you take a focused history. During a pelvic examination, you observe that her right ovary lacks mobility, and you map a number of trigger points for her pain. Transvaginal ultrasound results suggest the presence of nodules in the rectovaginal septum. You begin empiric treatment with continuous combined hormonal contraceptives to suppress menstruation. On her next visit, M.L. reports reduced but still bothersome pain. Laparoscopy reveals a 2-cm endometrioma in the right ovary and deep infiltrating lesions in the cul-de-sac. The endometrioma is resected. Histology confirms the diagnosis of endometriosis. 

REFERENCES
1. American College of Obstetricians and Gynecologists. Practice Bulletin #114: Management of endometriosis. Obstet Gynecol. 2010; 116(1):223-236.
2. Sanfilippo JS, Wakim NG, Schikler KN, Yussman MA. Endometriosis in association with uterine anomaly. Am J Obstet Gynecol. 1986; 154(1):39-43.
3. Taylor HS, Bagot C, Kardana A. HOX gene expression is altered in the endometrium of women with endometriosis. Hum Reprod. 1999; 14(5):1328-1331.
4. Berkley KJ, Stratton P. Mechanisms: lessons from translational studies of endometriosis. In: Giamberardino MA, ed. Visceral Pain: Clinical, Pathophysiological and Therapeutic Aspects. Oxford, UK: Oxford University Press; 2009:39-50.
5. Giudice LC. Clinical practice: endometriosis. N Engl J Med. 2010;362(25): 2389-2398.
6. Ballard K, Lowton K, Wright J. What’s the delay: a qualitative study of women’s experiences of reaching a diagnosis of endometriosis. Fertil Steril. 2006;86(5):1296-1301.
7. May KE, Conduit-Hulbert SA, Villar J, et al. Peripheral biomarkers of endometriosis: a systematic review. Hum Reprod Update. 2010; 16(6):651-674.
8. May KE, Villar J, Kirtley S, et al. Endometrial alterations in endometriosis: a systematic review of putative biomarkers. Hum Reprod Update. 2011; 17(5):637-653.
9. Tamaresis JS, Irwin JC, Goldfien GA, et al. Molecular classification of endometriosis and disease stage using high-dimensional genomic data. Endocrinology. 2014;155(12):4986-4999.
10. Sinaii N, Cleary SD, Ballweg ML, et al. High rates of autoimmune and endocrine disorders, fibromyalgia, chronic fatigue syndrome and atopic diseases among women with endometriosis: a survey analysis. Hum Reprod. 2002;17(10):2715-2724.
11. De Graaff AA, D’Hooghe TM, Dunselman GA, et al. The significant effect of endometriosis on physical, mental and social wellbeing: results from an international cross-sectional survey. Hum Reprod. 2013;28(10):2677-2685.
12. Lafay Pillet MC, Huchon C, Santulli P, et al. A clinical score can predict associated deep infiltrating endometriosis before surgery for an endometrioma. Hum Reprod. 2014;29(8):1666-1676.
13. Healey M, Cheng C, Kaur H. To excise or ablate endometriosis? A prospective randomized double-blinded trial after 5-year follow-up. J Minim Invasive Gynecol. 2014;21(6):999-1004.
14. Anaf V, El Nakadi I, De Moor V, et al. Increased nerve density in deep infiltrating endometriotic nodules. Gynecol Obstet Invest. 2011;71(2):112-117.
15. Stratton P, Berkley KJ. Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications. Hum Reprod Update. 2011;17(3):327-346.
16. Karp BI, Sinaii N, Nieman LK, et al. Migraine in women with chronic pelvic pain with and without endometriosis. Fertil Steril. 2011;95(3):895-899.
17. Berkley KJ. A life of pelvic pain. Physiol Behav. 2005;86(3):272-280.
18. Fauconnier A, Chapron C. Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications. Hum Reprod Update. 2005;11(6):595-606.
19. Vercellini P, Fedele L, Aimi G, et al. Association between endometriosis stage, lesion type, patient characteristics and severity of pelvic pain symptoms: a multivariate analysis of over 1000 patients. Hum Reprod. 2007;22(1):266-271.
20. Ling FW. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Pelvic Pain Study Group. Obstet Gynecol. 1999;93(1):51-58.
21. Muzii L, Di Tucci C, Di Feliciantonio M, et al. The effect of surgery for endometrioma on ovarian reserve evaluated by antral follicle count: a systematic review and meta-analysis. Hum Reprod. 2014;29(10):2190-2198.
22. Muzii L, Luciano AA, Zupi E, Panici PB. Effect of surgery for endometrioma on ovarian function: a different point of view. J Minim Invasive Gynecol. 2014;21(4):531-533.
23. Stegmann BJ, Sinaii N, Liu S, et al. Using location, color, size, and depth to characterize and identify endometriosis lesions in a cohort of 133 women. Fertil Steril. 2008;89(6):1632-1636.

Nausea and vomiting is common in cancer patients and a frequent presentation in the ED. When evaluating nausea and vomiting, the clinician should be aware that the two are not always linked—nausea may present without vomiting and vice versa. Nausea is “an unpleasant sensation of the need to vomit and is associated with autonomic symptoms,” whereas vomiting is “the forceful propulsion of abdominal contents via the contraction of the abdominal musculature and diaphragm.”¹ Whether these symptoms present together or independently of each other, both can result in serious metabolic disturbances, internal injury, malnutrition, and poor quality of life. In addition, nausea and vomiting can result in patient withdrawal from potentially beneficial treatment.² Based on the current literature, this article reviews and provides recommendations on appropriate assessment and treatment of the cancer patient presenting to the ED with nausea and/or vomiting.

Epidemiology

In 2007, the US Nationwide Emergency Department Sample database noted 122 million ED visits, 1.6 million of which were due to nausea and vomiting.³ In contrast, a small study from the United Kingdom cited 18% of ED visits in one of its centers were due to nausea and/or vomiting, demonstrating that the percentage of patients presenting with these symptoms can vary greatly.⁴

The incidence of cancer-related nausea and vomiting in the ED is unknown. Although EDs affiliated with large cancer centers see many cases of cancer-associated nausea and vomiting, presentations to noncancer-center EDs are becoming more prevalent due to increases in community-based cancer care.⁵ While the number of cancer patients is rising and the general population is aging,⁶ there is now less incidence of breakthrough chemotherapy-induced nausea and vomiting (CINV), which is a common cause of cancer-related nausea and vomiting. Older studies quote a 40% to 60% rate of breakthrough CINV; however, with the advent of newer antiemetic prophylaxis, by 2013 the incidence had decreased to about 28%.⁷ As such, the net effect may be a stable or decreased number of ED visits. In one study of patients with breakthrough CINV, 64% were treated inpatient, 26% outpatient, and 10% in the ED. The study, however, does not note how many of these inpatient visits originated in the ED, highlighting that this is an area in need of further study.⁸

Current knowledge about the epidemiology and etiology of non-CINV comes from end-of-life (EOL) palliative-care literature treatment guidelines, which are organized by cause (etiology-based antiemetic treatment [EBAT]).^9-11 Although one systematic review found that the EBAT approach “cannot be shown to be more effective than using a single antiemetic at effective doses,”¹² the etiologic framework is useful and can be applied to non-EOL patients. According to a systematic review on the prevalence of symptoms, nausea in advanced cancer patients ranged from 6% to 68%.⁶ Another review on cancer-related nausea and vomiting that cited studies conducted in the 1990s showed patients had increased nausea and vomiting as they approach EOL—ranging from 36% upon entering palliative-care programs to 71% in the final week of life.¹³ However, another systematic review citing more recent studies contradicts these findings, stating that in the last 2 weeks of life, nausea was less common (17%) than in patients who were not at the last 2 weeks of life (31%);¹⁴ the same was true of vomiting (20% vs 13%). This data perhaps implies that treatment of nausea and vomiting has improved over time for EOL patients. The same review also found that women were more likely to experience nausea and vomiting than men,¹⁴ a finding also seen in a 2011 prospective study of antiemetics for breakthrough CINV vomiting.¹⁵

When evaluating patients with cancer-associated nausea and vomiting, it is important to remember that these symptoms rarely occur in isolation. Most patients present with between seven and 15 other complaints, such as pain, weakness, fatigue, anorexia, constipation, dry mouth, early satiety, and dyspnea.¹⁶

Pathophysiology

To understand nausea and vomiting, it is helpful to review the emetic pathway. There are four areas that stimulate the central vomiting center located in the medulla oblongata. These are the cerebral cortex, the vestibular nucleus, the intestinal tract, and the chemoreceptor trigger zone (located on the floor of the fourth ventricle). With sufficient input from any of these to the vomiting center, nausea occurs, followed by the vomiting reflex. It is known that each of the input zones, as well as the vomiting center itself, have receptors for various substances, including the following:^1,13,17-20

·        Cerebral cortex: gamma-aminobutyric acid, histamine type 1 (H₁)

·        Vestibular nucleus: muscarinic acetylcholine receptor (AChM), H₁

·        Intestinal tract: 5 hydroxytryptamine type 3 (5-HT₃) or serotonin type 3 receptors, 5 hydroxytryptamine type 4 (5-HT₄) or serotonin type 3 receptors, dopamine type 2 (D2)

·        Chemoreceptor trigger zone: 5 hydroxytryptamine type 2 (5-HT₂) or serotonin type 2; D2, neurokinin-1 (NK1), or substance P

·        Vomiting center: AChM, H₁, 5-HT₂, D2, NK1, ([GK mµ] opioid receptors), and cannabinoid (CB) receptors

Each of the aforementioned substances in turn stimulate receptors in the intestinal tract and in the chemoreceptor trigger zone, triggering the vomiting center.^1,13,17 Most antiemetic agents block the receptors for one or more of these mediators and are discussed later in more detail. Chemotherapeutic agents specifically cause the release 5-HT and NK1 in the gut, which contains over 90% of the body’s serotonin. This knowledge has led to the development of newer 5-HT₃ and NK1 antagonists for CINV. Unlike the other mediators, cannabinoids cause an antiemetic effect when they bind to CB receptors.^13,17,19 This finding has led to the development of specific pharmacologic treatment agents. 

Etiology and Differential Diagnosis

Perhaps the best way for the emergency physician (EP) to assess the cancer patient with nausea or vomiting is to determine whether the cause is treatment- or nontreatment-related. Treatment-related causes are due to chemotherapy or radiotherapy, and any other causes would be considered nontreatment related. It is, however, wise for the EP to remember that a patient who has had recent chemotherapy can still be at risk for nontreatment etiologies.

Treatment-Related Nausea and Vomiting

Chemotherapy-Induced

Chemotherapy-induced nausea and vomiting has been well-studied in the literature. Chemotherapy is classified as highly, moderately, low, and minimally emetogenic.^18,19 Nausea itself is classified as acute (onset within 24 hours), delayed (onset after 24 hours), and anticipatory (prior to the chemotherapy, usually due to anxiety over previous unpleasant experiences). Breakthrough vomiting occurs despite the use of antiemetics and may be acute or delayed up to 5 days.

When evaluating the patient with recent chemotherapy and vomiting, it is prudent to find out if the agent is expected to cause vomiting. For example, a patient on cladribine, which is classified as minimally emetogenic, who experiences significant nausea and vomiting should likely be worked up for another etiology. Even when vomiting is controlled, a significant number of patients still experience nausea without vomiting, which in turn has a negative impact on quality of life.

Even though prophylactic regimens of 5-HT₃ and NK1 receptor antagonists have led to improved rates of CINV control,^18,19,21 both persistent nausea without vomiting and breakthrough vomiting remain problematic,¹⁸ and little scientific work has been done on breakthrough treatment. A small prospective pilot study of the efficacy of prochlorperazine versus serotonin 5-HT₃ receptor antagonists for breakthrough vomiting found both medications reduced nausea by 75% at 4 hours.¹⁵ In contrast, randomized controlled trials comparing olanzapine to metoclopramide and prochlorperazine for breakthrough vomiting found that at 3 days, olanzapine consistently achieved total relief of vomiting 66% to 70%, while the success rates of the other agents ranged from 20% to 37%.¹⁸

Radiotherapy-Induced

Radiotherapy has long been known to adversely affect the gastrointestinal (GI) tract. 5-HT₃ (ie, serotonin) is released from the gut enterochromaffin cells, in a manner similar to chemotherapy. A 2015 review on the subject showed that radiotherapy to the upper abdomen is most likely to lead to nausea and vomiting, with 50% to 67% of patients reporting nausea and 21% to 38% reporting vomiting.²⁰ Recommended prophylaxis and treatment regimens are based on consensus expert opinion, highlighting the lack of quality evidence that is seen with CINV. Prophylaxis regimens use 5-HT₃ antagonists prior to every session, plus dexamethasone for the first 5 days. Rescue from breakthrough is also treated with 5-HT₃ antagonists. The use of daily 5-HT₃ antagonists for a long course of radiotherapy, however, can be very expensive and unnecessary.

In addition, there is a delayed nausea and vomiting phenomena that may be due to substances other than serotonin, since 5-HT₃ depletes a few days after radiotherapy is begun, and may explain why 5-HT₃ antagonists are less effective after the first few days of radiotherapy. Nonpharmacologic treatments such as acupuncture, acupressure, hydrogen therapy, and ginger have been used or proposed as treatments for nausea, with mild benefit and little toxicity, so they should be studied further.²⁰

Nontreatment-Related Nausea or Vomiting

·        Impaired gastric emptying due to tumor or hepatomegaly, bowel obstruction, metabolic problems (eg, renal failure, liver failure, hypercalcemia, hyponatremia, ketoacidosis)

·        infection

·        drugs

·        increased intracranial pressure (ICP)

·        anxiety

The above causes of nausea and vomiting accounted for 85% of the cases in the study.⁹ Similar results were found in another study, showing that impaired gastric emptying and metabolic/drugs each caused about one third of the cases.¹⁰

Nontreatment-related causes of nausea and vomiting are traditionally divided into the following six broad etiological categories by palliative care practitioners^9,10,13:

1.  Biochemical: medications, tumor products, metabolic derangements, comorbidities, including systemic infections, noncancer abdominal illnesses; and silent cardiac ischemia

2.  Gastric stasis: tumor, neuropathy, hepatomegaly, ascites

3.  Bowel dysmotility/obstruction: tumor, metastases, adhesions, ileus, constipation

4.  Intracranial pressure: tumor edema, bleeding, hydrocephalus, leptomeningeal disease

5.  Vestibular: opioids, comorbid vestibular problems, brainstem metastases

6.  Miscellaneous: anxiety, pain

  These classification schemes are designed to help guide the treatment of palliative-care patients (EBAT),^9-11 but very little evidence supports the recommendations.^11-13,17 Expert opinion consensus guidelines favor haloperidol for biochemical etiology and metoclopramide for impaired gastric emptying. In intestinal obstruction, the H₁-blocking antihistamine cyclizine and the anticholinergic hyoscine butylbromide (scopoloamine) are the preferred agents, but dexamethasone and haloperidol are also favored by some. It is believed that increased ICP nausea is best treated with cyclizine and dexamethasone. Vestibular etiologies are treated with cyclizine, and anxiety-mediated nausea should be treated with benzodiazepines.^9,17 As there are often multiple etiologies in a given patient, selection of one agent can be problematic.¹³ Furthermore, no studies have applied these guidelines to ED cancer patients. This framework, however, can assist the EP in forming a differential diagnosis and appropriate workup. On history and physical examination, the EP should look for and consider the following:^13,16

·        Small-volume undigested emesis shortly after eating, suggesting gastric emptying impairment

·        Bilious or feculent vomitus, large volumes, constipation, and obstipation, suggesting bowel obstruction (evaluate via X-ray or computed tomographic imaging)

·        Early morning nausea and headache, suggesting increased ICP

·        Nausea associated with head movement or motion, with or without vertigo, (suggesting vestibular disease)

·        Current or recent use of opioids, antibiotics, antifungals, anticonvulsants, vitamins, ethanol, and selective serotonin reuptake inhibitors

·        Infection, sepsis

·        Metabolic abnormalities found on blood tests (for example, renal failure, liver failure, hypercalcemia, hyponatremia, ketoacidosis, osmolar gap, toxins/poisons, Addisonian crisis from steroid withdrawal or adrenal metastases); and/or

·        Silent cardiac ischemia (evaluate via electrocardiography and cardiac enzymes)

·        Careful consideration of each of the above possibilities will make one less likely to miss other serious causes of nausea and vomiting in the cancer patient with recent chemotherapy.

Opioid-Induced Nausea

Forty percent of cancer patients taking opioids experience nausea, which can adversely impact pain control.²² Opioid-induced nausea is due to constipation, gastroparesis, stimulation of the chemoreceptor trigger zone, and sensitization of the labyrinth, all of which can in turn stimulate the vomiting center.

Regarding the treatment of opioid-induced nausea and vomiting, there is no evidence to support the use of one antiemetic over another. Some weak evidence-based recommendations suggest either changing the medication to a different opioid, or changing the route of administration from oral to subcutaneous and adding coanalgesics such as gabapentin or ketamine to reduce opioid dosages. Though these strategies may be helpful in practice, none of the studies was large enough or thorough enough to support or warrant any formal recommendations in this systematic review.²²

Initial Management and Treatment

As always, attention to the patient’s airway, breathing, and circulation is of utmost importance. Endotracheal intubation should be considered in patients at risk for aspiration—unless a living will or do-not-resuscitate order exists. Maneuvers such as raising the head of the bed or turning the patient on his or her side may help avoid aspiration.

Intravenous (IV) hydration is generally beneficial. The choice and amount of fluid should be based on clinical judgment. Electrolyte imbalances should be corrected. The mainstay of treatment for nausea and/or vomiting is pharmacologic, which is the focus of the next section.

Pharmacologic Management

Prokinetic Agents

Prokinetic agents increase peristalsis and exert an antiemetic effect. Metoclopramide is the best known and most widely available prokinetic agent. Since it is both inexpensive and very effective as an antiemetic, its use in the ED is widespread. Etiology-based antiemetic treatment guidelines list metoclopramide as the antiemetic of choice when gastroparesis or other gastric emptying problems are diagnosed^9,10,13,17 as it exerts both D2 and 5-HT₃ central nervous system (CNS) antiemetic effects, relaxes pyloric tone (D2), and increases peristalsis by stimulating 5-HT₄ serotonin receptors in the gut.

The main limitation of metoclopramide is its extrapyramidal side effects (eg, akathisia, dystonia, psuedoparkinsonism, dyskinesia). Akathisias (ie, restlessness) is a particularly common phenomenon in patients taking metoclopramide. Patients experiencing extrapyramidal reactions are typically treated with diphenhydramine. In addition to the extrapyramidal side effects, metoclopramide is relatively contraindicated in patients with complete bowel obstruction.^13,17

In addition to metoclopramide, erythromycin and mirtazapine are other prokinetic agents used in palliative care. Erythromycin has mainly been used for diabetic gastroparesis due to its stimulatory effect on motilin receptors in the GI tract.^13,23 Mirtazapine is an antidepressant with both 5-HT₃ and 5-HT₄ receptor activity. In one case report it was used to treat gastroparesis refractory to all other therapies, including metoclopramide and erythromycin.²³

Dopamine-Receptor Antagonists

This category includes many agents, most which are known for their antipsychotic effects. The primary mode of action of dopamine-receptor antagonists is to block D2 receptors in the vomiting center. Etiology-based antiemetic treatment guidelines list these drugs as the first choice in patients with a biochemical-based etiology for nausea, though there is little-to-no evidence to support this recommendation.^{9,10,12,13,17}

While a review on haloperidol use in cancer found its effects better than placebo for CINV and postoperative nausea, studies in the review were small and the evidence weak.²⁴ Due to its low cost, and comparatively favorable side-effect profile, haloperidol is a reasonable alternative to metoclopramide. Indeed, if palliative-care models are used, haloperidol would be preferred over metoclopramide since biochemical nausea is probably more prevalent in the general ED cancer patient than gastroparesis.

Regarding route of administration, olanzapine can be given orally or intramuscularly, making it potentially useful in the ED setting for those who cannot keep pills down and have poor venous access. When used in the supportive care setting, however, olanzapine is typically given at bedtime due to its sedative effects. As such, this agent may be best given to those who will be admitted or placed on observation status, since some patients may not be able to be discharged even if nausea resolves.

Antihistamine Agents

Cyclizine, diphenhydramine, hydroxyzine, meclozine, and promethazine, are all piperazine H₁-receptor blockers that work in the vomiting center, vestibular nucleus, and chemoreceptor trigger zone. In addition to its properties as an H₁-receptor antagonist, cyclizine also exhibits some anticholinergic activity that decreases bowel secretions, thus making it theoretically beneficial in patients with bowel obstruction. Each of these antihistamines are considered beneficial in treating nausea due to vestibular dysfunction and in motion sickness, and may be helpful in patients with increased ICP. Heavy sedation, anticholinergic, and extrapyramidal side effects may occur with these drugs, especially in elderly patients.^1,13,17

Serotonin 5-HT3 Receptor Antagonists

Dolasetron, granisetron, ondansetron, palonosetron, and tropisetron are among the 5-HT₃ (serotonin type 3) receptor antagonists used to treat nausea and vomiting. As previously stated, chemotherapy stimulates release of 5-HT from the gut, which in turn stimulates 5-HT₃ receptors in the gut, vagus nerve, and the chemotherapy trigger zone—all of which in turn stimulate the vomiting center, leading to the vomiting reflex.^{1,13,17,19,21} The blocking action of these drugs on the 5-HT₃ receptors is the basis of the antiemetic effect. Palonosetron, with its long 40-hour half-life, has become the preferred prophylactic agent for CINV. The most common adverse events with 5-HT₃ antagonists include mild headache, transient elevation of hepatic aminotransferase levels, and constipation.^19,21 The use of ondansetron for emesis in the ED is becoming more established both for CINV and non-CINV—mainly due to its high efficacy and favorable side-effect profile compared to metoclopramide and the dopamine antagonists.

Substance P Antagonists (NK1-Receptor Antagonists)

Oral aprepitant, injectable fosaprepitant, and netupitant are some of the Substance P (NK1) antagonists used to treat nausea and vomiting. In a manner similar to 5-HT release, chemotherapeutic agents stimulate the cellular release of NK1 in the gut. This reaction in turn activates receptors in the vagus nerve and the chemotherapy trigger zone, which stimulates the vomiting center. The NK1 receptors are blocked by these agents. The main use of these medications has been to complement the 5-HT₃ antagonists for prophylaxis prior to administration of chemotherapy. Neurokinin-1receptor antagonists have not been studied in the setting of breakthrough nausea and vomiting but they are being used to treat delayed phase breakthrough CINV by the authors at their institution’s ED.  The agents  have been shown to be more effective than 5-HT₃ agents in preventing delayed phase nausea and vomiting.²⁵ As such, the possibility they may also be effective in treating delayed phase breakthrough CINV has led to this use. Recent studies have found these agents highly effective in the treatment of postoperative nausea and vomiting in high-risk patients.²⁶ 

The standard in recent years for prophylaxis has been combining 5-HT₃ antagonists, NK1 inhibitors, and dexamethasone. Netupitant/palonosetron (commonly referred to as NEPA) is a novel oral agent combining a long-acting 5-HT₃ antagonist, and a long-acting NK1 inhibitor for CINV prophylaxis.²⁷ Its use in treating delayed breakthrough vomiting remains to be seen.

Corticosteroids

Based on its antiemetic properties, the corticosteroid dexamethasone increases the effects of antiemetics (ie, metoclopramide and more recently 5-HT₃ and NK1 receptor antagonists) in preventing CINV, perhaps by reducing the blood-brain barrier permeability to emetogenic substances. There are also some evidence-based benefits in using dexamethasone in patients with bowel obstruction. It is also used to reduce ICP from cerebral edema.^{1,11,13,17,19}

Benzodiazepines

The benzodiazepines are best given to enhance the antiemetic effects of other drugs, especially in patients experiencing anxiety-related side effects. The benzodiazepines work well for anticipatory nausea. Lorazepam is the preferred drug of choice due to the lack of active metabolites. However, the clinician should always exercise caution when using benzodiazepines in elderly patients due to the increased risk of falls and cognitive impairment.^13,17,19

Cannabinoids

The observation that the incidence of CINV decreased in marijuana smokers led to the exploration of cannabinoids for the treatment of nausea and vomiting. Tetrahydrocannabinol, the psychoactive substance in marijuana, is a phytocannabinoid. Its receptor, CB1, exists throughout the brain. Synthetic cannabinoids such as oral dronabinol, oral nabilone, and intramuscular levonantradol have been used with antiemetic success superior to chlorpromazine, haloperidol, metoclopramide, and prochlorperazine, but at the cost of unpleasant CNS effects and postural hypotension in elderly patients.^1,13,17

As cited in a systematic review, cannabinoids appear to inhibit growth of glioblastoma multiforme, breast, prostate, and thyroid cancer, colon carcinoma, leukemia, and lymphomas. Cannabinoids can also benefit cancer patients by stimulating appetite, elevating mood, and inhibiting pain.²⁸ Clearly, more oncologic research needs to be done on the topic. As such, this class of medication is years, if not decades, away from use in the ED.

Nonpharmacologic Treatments

Acupuncture and Acupressure

A 2006 Cochrane systematic review and meta-analysis showed that acupuncture helped with acute CINV but not with delayed CINV.²⁹ Acupuncture was shown to work best with electro-acupuncture needles. Acupressure without needles helped nausea but not vomiting.²⁹ A more recent review on the specific P6 acupuncture area on the wrist near the median nerve found that electroacupuncture, but not manual acupuncture, was beneficial for first-day vomiting, and acupressure was effective for first-day nausea but not vomiting. Neither acupuncture nor acupressure was shown to help delayed nausea or vomiting.³⁰

Ginger

Ginger has been shown to help with CINV and anticipatory nausea, but not with other types of nausea.¹³ Supplementing routine antiemetics with 0.5 to 1.5 g of ginger per day for 6 days (beginning 3 days before chemotherapy) was shown to reduce the severity of nausea on the day of chemotherapy, but did not affect vomiting.²¹

Percutaneous Gastrostomy, Stenting, and Laser Therapy

Several strategies have been developed for palliation of intestinal obstruction when surgery is not warranted. Percutaneous gastrostomy tubes (PEG) are used to vent GI secretions that would otherwise build up. Esophageal, colorectal, and gastric outlet obstructions can be palliated by endoscopically placed stenting devices. Argon beam plasma coagulation laser therapy can be used for gastric outlet as well as colonic obstruction.^13,31 One review evaluating the benefits of colonic obstruction stenting found an 89% success rate in symptom relief. This same review noted that venting the PEG tube placement had an 84% rate of symptom relief.³¹

Selecting an Agent in the ED: the Evidence (or Lack Thereof)

Nontreatment-Related Nausea and Vomiting

A 2011 systematic review of cancer nausea unrelated to chemotherapy or radiotherapy found level B evidence that metoclopramide is the most effective first-line empiric agent. In patients with bowel obstruction, dexamethasone, hyoscine butylbromide (scopolamine), and octreotide are effective. While dexamethasone is often thought to improve the effects of antiemetic drugs, this review showed it did not improve nausea when added to chlorpromazine or metoclopramide. Furthermore, neither metoclopramide nor ondansetron were shown to reduce opioid-induced emesis.¹³ The review further pointed out the lack of good evidence for expert opinion guideline recommendations in breakthrough vomiting—eg, dose titration of the same drug, switching to a different drug class, or using two or more drugs together at once.¹³

Another review had similar findings, while pointing out that an “absence of evidence is not evidence of absence,” and noting that many of these treatments have been used for years—ie, the problem is lack of evidence, but not negative evidence.¹⁷ Both studies are notable in that they were all done in palliative-care units in which time to relief from nausea and/or vomiting was typically measured in days, not hours, making their application to the emergency setting—where time is a factor—difficult.

Due to the potential for drug toxicity, using the same antiemetic drug repeatedly within a short amount of time in a patient refractory to therapy may not be the best strategy in the ED. It is most likely more beneficial and effective to switch drugs or use a combination of drugs right away—though this approach has theoretical concerns with drug-drug interactions. Again, this is an area in which further study is needed.

Treatment-Related Nausea and Vomiting

A recent review on breakthrough CINV again cited the paucity of clinical trials for this entity. Based on few studies, olanzapine and metoclopramide seem to be of value when prophylactic antiemetic regimens have failed. The review further noted that treatment of breakthrough CINV with an agent from same drug class as that used in the prophylactic regimen (usually 5-HT₃ and NK1 antagonists) is unlikely to be successful.³² This review also mentioned an interesting phase 2 study using a transdermal gel consisting of diphenhydramine, haloperidol, and lorazepam to the wrist, in which 27 of 33 patients in the study reported a decrease in nausea within a 4-hour period.³³ The same combination of drugs in IV form (lorazepam 0.5 mg, diphenhydramine 12.5 mg, and haloperidol 1 mg) is frequently used in the ED at the authors’ institution to treat breakthrough vomiting refractory to metoclopramide, antihistamines, or 5-HT₃ antagonists. To the authors’ knowledge, this combination treatment has not been previously cited in the medical literature.

Recommendations and Summary

Cancer patients presenting to the ED with nausea and vomiting should be thoroughly evaluated regarding the possible etiology of their symptoms. A careful history must include recent chemotherapy, radiation, medications, as well as knowledge of the potential complications associated with the specific type of cancer. The EP also should keep in mind that delayed nausea and vomiting can be present several days after chemotherapy, and that CINV may not manifest until after the initial prophylactic medications have worn off. Moreover, he or she should be aware that some individuals have unique responses to chemotherapy and radiation and may experience more nausea and vomiting symptoms than is considered typical.

In addition to CINV, other etiologies, including GI issues such as delayed gastric emptying, partial bowel obstruction, and constipation should also be carefully considered. When evaluating the patient, the EP should also consider non-GI causes such as elevated ICP, kidney obstruction, infection, silent cardiac ischemia, steroid withdrawal, Addisonian crisis, and electrolyte abnormalities.

The lack of conclusive evidence for the treatment of cancer-related nausea and vomiting in any circumstance—except for prophylaxis prior to chemotherapy—precludes the recommendation of a specific treatment algorithm. However, the evidence is abundant that there are multiple effective agents with different, if not overlapping, mechanisms of action available. The EP, therefore, should be familiar with the most commonly used antiemetic drugs from several different categories and their side effects, and tailor the approach based on the assumed etiology of the symptoms. When treating CINV or cancer-related nausea and vomiting, it is not uncommon that patients may require multiple agents, either simultaneously or in sequence, to obtain symptom resolution.

Dr Sandoval is an assistant professor, department of emergency medicine, division of internal medicine at The University of Texas MD Anderson Cancer Center, Houston. Dr Rice is an assistant professor and clinical medical director in the department of emergency medicine, division of internal medicine at The University of Texas MD Anderson Cancer Center, Houston.

Nausea and vomiting is common in cancer patients and a frequent presentation in the ED. When evaluating nausea and vomiting, the clinician should be aware that the two are not always linked—nausea may present without vomiting and vice versa. Nausea is “an unpleasant sensation of the need to vomit and is associated with autonomic symptoms,” whereas vomiting is “the forceful propulsion of abdominal contents via the contraction of the abdominal musculature and diaphragm.”¹ Whether these symptoms present together or independently of each other, both can result in serious metabolic disturbances, internal injury, malnutrition, and poor quality of life. In addition, nausea and vomiting can result in patient withdrawal from potentially beneficial treatment.² Based on the current literature, this article reviews and provides recommendations on appropriate assessment and treatment of the cancer patient presenting to the ED with nausea and/or vomiting.

Epidemiology

In 2007, the US Nationwide Emergency Department Sample database noted 122 million ED visits, 1.6 million of which were due to nausea and vomiting.³ In contrast, a small study from the United Kingdom cited 18% of ED visits in one of its centers were due to nausea and/or vomiting, demonstrating that the percentage of patients presenting with these symptoms can vary greatly.⁴

The incidence of cancer-related nausea and vomiting in the ED is unknown. Although EDs affiliated with large cancer centers see many cases of cancer-associated nausea and vomiting, presentations to noncancer-center EDs are becoming more prevalent due to increases in community-based cancer care.⁵ While the number of cancer patients is rising and the general population is aging,⁶ there is now less incidence of breakthrough chemotherapy-induced nausea and vomiting (CINV), which is a common cause of cancer-related nausea and vomiting. Older studies quote a 40% to 60% rate of breakthrough CINV; however, with the advent of newer antiemetic prophylaxis, by 2013 the incidence had decreased to about 28%.⁷ As such, the net effect may be a stable or decreased number of ED visits. In one study of patients with breakthrough CINV, 64% were treated inpatient, 26% outpatient, and 10% in the ED. The study, however, does not note how many of these inpatient visits originated in the ED, highlighting that this is an area in need of further study.⁸

Current knowledge about the epidemiology and etiology of non-CINV comes from end-of-life (EOL) palliative-care literature treatment guidelines, which are organized by cause (etiology-based antiemetic treatment [EBAT]).^9-11 Although one systematic review found that the EBAT approach “cannot be shown to be more effective than using a single antiemetic at effective doses,”¹² the etiologic framework is useful and can be applied to non-EOL patients. According to a systematic review on the prevalence of symptoms, nausea in advanced cancer patients ranged from 6% to 68%.⁶ Another review on cancer-related nausea and vomiting that cited studies conducted in the 1990s showed patients had increased nausea and vomiting as they approach EOL—ranging from 36% upon entering palliative-care programs to 71% in the final week of life.¹³ However, another systematic review citing more recent studies contradicts these findings, stating that in the last 2 weeks of life, nausea was less common (17%) than in patients who were not at the last 2 weeks of life (31%);¹⁴ the same was true of vomiting (20% vs 13%). This data perhaps implies that treatment of nausea and vomiting has improved over time for EOL patients. The same review also found that women were more likely to experience nausea and vomiting than men,¹⁴ a finding also seen in a 2011 prospective study of antiemetics for breakthrough CINV vomiting.¹⁵

When evaluating patients with cancer-associated nausea and vomiting, it is important to remember that these symptoms rarely occur in isolation. Most patients present with between seven and 15 other complaints, such as pain, weakness, fatigue, anorexia, constipation, dry mouth, early satiety, and dyspnea.¹⁶

Pathophysiology

To understand nausea and vomiting, it is helpful to review the emetic pathway. There are four areas that stimulate the central vomiting center located in the medulla oblongata. These are the cerebral cortex, the vestibular nucleus, the intestinal tract, and the chemoreceptor trigger zone (located on the floor of the fourth ventricle). With sufficient input from any of these to the vomiting center, nausea occurs, followed by the vomiting reflex. It is known that each of the input zones, as well as the vomiting center itself, have receptors for various substances, including the following:^1,13,17-20

·        Cerebral cortex: gamma-aminobutyric acid, histamine type 1 (H₁)

·        Vestibular nucleus: muscarinic acetylcholine receptor (AChM), H₁

·        Intestinal tract: 5 hydroxytryptamine type 3 (5-HT₃) or serotonin type 3 receptors, 5 hydroxytryptamine type 4 (5-HT₄) or serotonin type 3 receptors, dopamine type 2 (D2)

·        Chemoreceptor trigger zone: 5 hydroxytryptamine type 2 (5-HT₂) or serotonin type 2; D2, neurokinin-1 (NK1), or substance P

·        Vomiting center: AChM, H₁, 5-HT₂, D2, NK1, ([GK mµ] opioid receptors), and cannabinoid (CB) receptors

Each of the aforementioned substances in turn stimulate receptors in the intestinal tract and in the chemoreceptor trigger zone, triggering the vomiting center.^1,13,17 Most antiemetic agents block the receptors for one or more of these mediators and are discussed later in more detail. Chemotherapeutic agents specifically cause the release 5-HT and NK1 in the gut, which contains over 90% of the body’s serotonin. This knowledge has led to the development of newer 5-HT₃ and NK1 antagonists for CINV. Unlike the other mediators, cannabinoids cause an antiemetic effect when they bind to CB receptors.^13,17,19 This finding has led to the development of specific pharmacologic treatment agents. 

Etiology and Differential Diagnosis

Perhaps the best way for the emergency physician (EP) to assess the cancer patient with nausea or vomiting is to determine whether the cause is treatment- or nontreatment-related. Treatment-related causes are due to chemotherapy or radiotherapy, and any other causes would be considered nontreatment related. It is, however, wise for the EP to remember that a patient who has had recent chemotherapy can still be at risk for nontreatment etiologies.

Treatment-Related Nausea and Vomiting

Chemotherapy-Induced

Chemotherapy-induced nausea and vomiting has been well-studied in the literature. Chemotherapy is classified as highly, moderately, low, and minimally emetogenic.^18,19 Nausea itself is classified as acute (onset within 24 hours), delayed (onset after 24 hours), and anticipatory (prior to the chemotherapy, usually due to anxiety over previous unpleasant experiences). Breakthrough vomiting occurs despite the use of antiemetics and may be acute or delayed up to 5 days.

When evaluating the patient with recent chemotherapy and vomiting, it is prudent to find out if the agent is expected to cause vomiting. For example, a patient on cladribine, which is classified as minimally emetogenic, who experiences significant nausea and vomiting should likely be worked up for another etiology. Even when vomiting is controlled, a significant number of patients still experience nausea without vomiting, which in turn has a negative impact on quality of life.

Even though prophylactic regimens of 5-HT₃ and NK1 receptor antagonists have led to improved rates of CINV control,^18,19,21 both persistent nausea without vomiting and breakthrough vomiting remain problematic,¹⁸ and little scientific work has been done on breakthrough treatment. A small prospective pilot study of the efficacy of prochlorperazine versus serotonin 5-HT₃ receptor antagonists for breakthrough vomiting found both medications reduced nausea by 75% at 4 hours.¹⁵ In contrast, randomized controlled trials comparing olanzapine to metoclopramide and prochlorperazine for breakthrough vomiting found that at 3 days, olanzapine consistently achieved total relief of vomiting 66% to 70%, while the success rates of the other agents ranged from 20% to 37%.¹⁸

Radiotherapy-Induced

Radiotherapy has long been known to adversely affect the gastrointestinal (GI) tract. 5-HT₃ (ie, serotonin) is released from the gut enterochromaffin cells, in a manner similar to chemotherapy. A 2015 review on the subject showed that radiotherapy to the upper abdomen is most likely to lead to nausea and vomiting, with 50% to 67% of patients reporting nausea and 21% to 38% reporting vomiting.²⁰ Recommended prophylaxis and treatment regimens are based on consensus expert opinion, highlighting the lack of quality evidence that is seen with CINV. Prophylaxis regimens use 5-HT₃ antagonists prior to every session, plus dexamethasone for the first 5 days. Rescue from breakthrough is also treated with 5-HT₃ antagonists. The use of daily 5-HT₃ antagonists for a long course of radiotherapy, however, can be very expensive and unnecessary.

In addition, there is a delayed nausea and vomiting phenomena that may be due to substances other than serotonin, since 5-HT₃ depletes a few days after radiotherapy is begun, and may explain why 5-HT₃ antagonists are less effective after the first few days of radiotherapy. Nonpharmacologic treatments such as acupuncture, acupressure, hydrogen therapy, and ginger have been used or proposed as treatments for nausea, with mild benefit and little toxicity, so they should be studied further.²⁰

Nontreatment-Related Nausea or Vomiting

·        Impaired gastric emptying due to tumor or hepatomegaly, bowel obstruction, metabolic problems (eg, renal failure, liver failure, hypercalcemia, hyponatremia, ketoacidosis)

·        infection

·        drugs

·        increased intracranial pressure (ICP)

·        anxiety

The above causes of nausea and vomiting accounted for 85% of the cases in the study.⁹ Similar results were found in another study, showing that impaired gastric emptying and metabolic/drugs each caused about one third of the cases.¹⁰

Nontreatment-related causes of nausea and vomiting are traditionally divided into the following six broad etiological categories by palliative care practitioners^9,10,13:

1.  Biochemical: medications, tumor products, metabolic derangements, comorbidities, including systemic infections, noncancer abdominal illnesses; and silent cardiac ischemia

2.  Gastric stasis: tumor, neuropathy, hepatomegaly, ascites

3.  Bowel dysmotility/obstruction: tumor, metastases, adhesions, ileus, constipation

4.  Intracranial pressure: tumor edema, bleeding, hydrocephalus, leptomeningeal disease

5.  Vestibular: opioids, comorbid vestibular problems, brainstem metastases

6.  Miscellaneous: anxiety, pain

  These classification schemes are designed to help guide the treatment of palliative-care patients (EBAT),^9-11 but very little evidence supports the recommendations.^11-13,17 Expert opinion consensus guidelines favor haloperidol for biochemical etiology and metoclopramide for impaired gastric emptying. In intestinal obstruction, the H₁-blocking antihistamine cyclizine and the anticholinergic hyoscine butylbromide (scopoloamine) are the preferred agents, but dexamethasone and haloperidol are also favored by some. It is believed that increased ICP nausea is best treated with cyclizine and dexamethasone. Vestibular etiologies are treated with cyclizine, and anxiety-mediated nausea should be treated with benzodiazepines.^9,17 As there are often multiple etiologies in a given patient, selection of one agent can be problematic.¹³ Furthermore, no studies have applied these guidelines to ED cancer patients. This framework, however, can assist the EP in forming a differential diagnosis and appropriate workup. On history and physical examination, the EP should look for and consider the following:^13,16

·        Small-volume undigested emesis shortly after eating, suggesting gastric emptying impairment

·        Bilious or feculent vomitus, large volumes, constipation, and obstipation, suggesting bowel obstruction (evaluate via X-ray or computed tomographic imaging)

·        Early morning nausea and headache, suggesting increased ICP

·        Nausea associated with head movement or motion, with or without vertigo, (suggesting vestibular disease)

·        Current or recent use of opioids, antibiotics, antifungals, anticonvulsants, vitamins, ethanol, and selective serotonin reuptake inhibitors

·        Infection, sepsis

·        Metabolic abnormalities found on blood tests (for example, renal failure, liver failure, hypercalcemia, hyponatremia, ketoacidosis, osmolar gap, toxins/poisons, Addisonian crisis from steroid withdrawal or adrenal metastases); and/or

·        Silent cardiac ischemia (evaluate via electrocardiography and cardiac enzymes)

·        Careful consideration of each of the above possibilities will make one less likely to miss other serious causes of nausea and vomiting in the cancer patient with recent chemotherapy.

Opioid-Induced Nausea

Forty percent of cancer patients taking opioids experience nausea, which can adversely impact pain control.²² Opioid-induced nausea is due to constipation, gastroparesis, stimulation of the chemoreceptor trigger zone, and sensitization of the labyrinth, all of which can in turn stimulate the vomiting center.

Regarding the treatment of opioid-induced nausea and vomiting, there is no evidence to support the use of one antiemetic over another. Some weak evidence-based recommendations suggest either changing the medication to a different opioid, or changing the route of administration from oral to subcutaneous and adding coanalgesics such as gabapentin or ketamine to reduce opioid dosages. Though these strategies may be helpful in practice, none of the studies was large enough or thorough enough to support or warrant any formal recommendations in this systematic review.²²

Initial Management and Treatment

As always, attention to the patient’s airway, breathing, and circulation is of utmost importance. Endotracheal intubation should be considered in patients at risk for aspiration—unless a living will or do-not-resuscitate order exists. Maneuvers such as raising the head of the bed or turning the patient on his or her side may help avoid aspiration.

Intravenous (IV) hydration is generally beneficial. The choice and amount of fluid should be based on clinical judgment. Electrolyte imbalances should be corrected. The mainstay of treatment for nausea and/or vomiting is pharmacologic, which is the focus of the next section.

Pharmacologic Management

Prokinetic Agents

Prokinetic agents increase peristalsis and exert an antiemetic effect. Metoclopramide is the best known and most widely available prokinetic agent. Since it is both inexpensive and very effective as an antiemetic, its use in the ED is widespread. Etiology-based antiemetic treatment guidelines list metoclopramide as the antiemetic of choice when gastroparesis or other gastric emptying problems are diagnosed^9,10,13,17 as it exerts both D2 and 5-HT₃ central nervous system (CNS) antiemetic effects, relaxes pyloric tone (D2), and increases peristalsis by stimulating 5-HT₄ serotonin receptors in the gut.

The main limitation of metoclopramide is its extrapyramidal side effects (eg, akathisia, dystonia, psuedoparkinsonism, dyskinesia). Akathisias (ie, restlessness) is a particularly common phenomenon in patients taking metoclopramide. Patients experiencing extrapyramidal reactions are typically treated with diphenhydramine. In addition to the extrapyramidal side effects, metoclopramide is relatively contraindicated in patients with complete bowel obstruction.^13,17

In addition to metoclopramide, erythromycin and mirtazapine are other prokinetic agents used in palliative care. Erythromycin has mainly been used for diabetic gastroparesis due to its stimulatory effect on motilin receptors in the GI tract.^13,23 Mirtazapine is an antidepressant with both 5-HT₃ and 5-HT₄ receptor activity. In one case report it was used to treat gastroparesis refractory to all other therapies, including metoclopramide and erythromycin.²³

Dopamine-Receptor Antagonists

This category includes many agents, most which are known for their antipsychotic effects. The primary mode of action of dopamine-receptor antagonists is to block D2 receptors in the vomiting center. Etiology-based antiemetic treatment guidelines list these drugs as the first choice in patients with a biochemical-based etiology for nausea, though there is little-to-no evidence to support this recommendation.^{9,10,12,13,17}

While a review on haloperidol use in cancer found its effects better than placebo for CINV and postoperative nausea, studies in the review were small and the evidence weak.²⁴ Due to its low cost, and comparatively favorable side-effect profile, haloperidol is a reasonable alternative to metoclopramide. Indeed, if palliative-care models are used, haloperidol would be preferred over metoclopramide since biochemical nausea is probably more prevalent in the general ED cancer patient than gastroparesis.

Regarding route of administration, olanzapine can be given orally or intramuscularly, making it potentially useful in the ED setting for those who cannot keep pills down and have poor venous access. When used in the supportive care setting, however, olanzapine is typically given at bedtime due to its sedative effects. As such, this agent may be best given to those who will be admitted or placed on observation status, since some patients may not be able to be discharged even if nausea resolves.

Antihistamine Agents

Cyclizine, diphenhydramine, hydroxyzine, meclozine, and promethazine, are all piperazine H₁-receptor blockers that work in the vomiting center, vestibular nucleus, and chemoreceptor trigger zone. In addition to its properties as an H₁-receptor antagonist, cyclizine also exhibits some anticholinergic activity that decreases bowel secretions, thus making it theoretically beneficial in patients with bowel obstruction. Each of these antihistamines are considered beneficial in treating nausea due to vestibular dysfunction and in motion sickness, and may be helpful in patients with increased ICP. Heavy sedation, anticholinergic, and extrapyramidal side effects may occur with these drugs, especially in elderly patients.^1,13,17

Serotonin 5-HT3 Receptor Antagonists

Dolasetron, granisetron, ondansetron, palonosetron, and tropisetron are among the 5-HT₃ (serotonin type 3) receptor antagonists used to treat nausea and vomiting. As previously stated, chemotherapy stimulates release of 5-HT from the gut, which in turn stimulates 5-HT₃ receptors in the gut, vagus nerve, and the chemotherapy trigger zone—all of which in turn stimulate the vomiting center, leading to the vomiting reflex.^{1,13,17,19,21} The blocking action of these drugs on the 5-HT₃ receptors is the basis of the antiemetic effect. Palonosetron, with its long 40-hour half-life, has become the preferred prophylactic agent for CINV. The most common adverse events with 5-HT₃ antagonists include mild headache, transient elevation of hepatic aminotransferase levels, and constipation.^19,21 The use of ondansetron for emesis in the ED is becoming more established both for CINV and non-CINV—mainly due to its high efficacy and favorable side-effect profile compared to metoclopramide and the dopamine antagonists.

Substance P Antagonists (NK1-Receptor Antagonists)

Oral aprepitant, injectable fosaprepitant, and netupitant are some of the Substance P (NK1) antagonists used to treat nausea and vomiting. In a manner similar to 5-HT release, chemotherapeutic agents stimulate the cellular release of NK1 in the gut. This reaction in turn activates receptors in the vagus nerve and the chemotherapy trigger zone, which stimulates the vomiting center. The NK1 receptors are blocked by these agents. The main use of these medications has been to complement the 5-HT₃ antagonists for prophylaxis prior to administration of chemotherapy. Neurokinin-1receptor antagonists have not been studied in the setting of breakthrough nausea and vomiting but they are being used to treat delayed phase breakthrough CINV by the authors at their institution’s ED.  The agents  have been shown to be more effective than 5-HT₃ agents in preventing delayed phase nausea and vomiting.²⁵ As such, the possibility they may also be effective in treating delayed phase breakthrough CINV has led to this use. Recent studies have found these agents highly effective in the treatment of postoperative nausea and vomiting in high-risk patients.²⁶ 

The standard in recent years for prophylaxis has been combining 5-HT₃ antagonists, NK1 inhibitors, and dexamethasone. Netupitant/palonosetron (commonly referred to as NEPA) is a novel oral agent combining a long-acting 5-HT₃ antagonist, and a long-acting NK1 inhibitor for CINV prophylaxis.²⁷ Its use in treating delayed breakthrough vomiting remains to be seen.

Corticosteroids

Based on its antiemetic properties, the corticosteroid dexamethasone increases the effects of antiemetics (ie, metoclopramide and more recently 5-HT₃ and NK1 receptor antagonists) in preventing CINV, perhaps by reducing the blood-brain barrier permeability to emetogenic substances. There are also some evidence-based benefits in using dexamethasone in patients with bowel obstruction. It is also used to reduce ICP from cerebral edema.^{1,11,13,17,19}

Benzodiazepines

The benzodiazepines are best given to enhance the antiemetic effects of other drugs, especially in patients experiencing anxiety-related side effects. The benzodiazepines work well for anticipatory nausea. Lorazepam is the preferred drug of choice due to the lack of active metabolites. However, the clinician should always exercise caution when using benzodiazepines in elderly patients due to the increased risk of falls and cognitive impairment.^13,17,19

Cannabinoids

The observation that the incidence of CINV decreased in marijuana smokers led to the exploration of cannabinoids for the treatment of nausea and vomiting. Tetrahydrocannabinol, the psychoactive substance in marijuana, is a phytocannabinoid. Its receptor, CB1, exists throughout the brain. Synthetic cannabinoids such as oral dronabinol, oral nabilone, and intramuscular levonantradol have been used with antiemetic success superior to chlorpromazine, haloperidol, metoclopramide, and prochlorperazine, but at the cost of unpleasant CNS effects and postural hypotension in elderly patients.^1,13,17

As cited in a systematic review, cannabinoids appear to inhibit growth of glioblastoma multiforme, breast, prostate, and thyroid cancer, colon carcinoma, leukemia, and lymphomas. Cannabinoids can also benefit cancer patients by stimulating appetite, elevating mood, and inhibiting pain.²⁸ Clearly, more oncologic research needs to be done on the topic. As such, this class of medication is years, if not decades, away from use in the ED.

Nonpharmacologic Treatments

Acupuncture and Acupressure

A 2006 Cochrane systematic review and meta-analysis showed that acupuncture helped with acute CINV but not with delayed CINV.²⁹ Acupuncture was shown to work best with electro-acupuncture needles. Acupressure without needles helped nausea but not vomiting.²⁹ A more recent review on the specific P6 acupuncture area on the wrist near the median nerve found that electroacupuncture, but not manual acupuncture, was beneficial for first-day vomiting, and acupressure was effective for first-day nausea but not vomiting. Neither acupuncture nor acupressure was shown to help delayed nausea or vomiting.³⁰

Ginger

Ginger has been shown to help with CINV and anticipatory nausea, but not with other types of nausea.¹³ Supplementing routine antiemetics with 0.5 to 1.5 g of ginger per day for 6 days (beginning 3 days before chemotherapy) was shown to reduce the severity of nausea on the day of chemotherapy, but did not affect vomiting.²¹

Percutaneous Gastrostomy, Stenting, and Laser Therapy

Several strategies have been developed for palliation of intestinal obstruction when surgery is not warranted. Percutaneous gastrostomy tubes (PEG) are used to vent GI secretions that would otherwise build up. Esophageal, colorectal, and gastric outlet obstructions can be palliated by endoscopically placed stenting devices. Argon beam plasma coagulation laser therapy can be used for gastric outlet as well as colonic obstruction.^13,31 One review evaluating the benefits of colonic obstruction stenting found an 89% success rate in symptom relief. This same review noted that venting the PEG tube placement had an 84% rate of symptom relief.³¹

Selecting an Agent in the ED: the Evidence (or Lack Thereof)

Nontreatment-Related Nausea and Vomiting

A 2011 systematic review of cancer nausea unrelated to chemotherapy or radiotherapy found level B evidence that metoclopramide is the most effective first-line empiric agent. In patients with bowel obstruction, dexamethasone, hyoscine butylbromide (scopolamine), and octreotide are effective. While dexamethasone is often thought to improve the effects of antiemetic drugs, this review showed it did not improve nausea when added to chlorpromazine or metoclopramide. Furthermore, neither metoclopramide nor ondansetron were shown to reduce opioid-induced emesis.¹³ The review further pointed out the lack of good evidence for expert opinion guideline recommendations in breakthrough vomiting—eg, dose titration of the same drug, switching to a different drug class, or using two or more drugs together at once.¹³

Another review had similar findings, while pointing out that an “absence of evidence is not evidence of absence,” and noting that many of these treatments have been used for years—ie, the problem is lack of evidence, but not negative evidence.¹⁷ Both studies are notable in that they were all done in palliative-care units in which time to relief from nausea and/or vomiting was typically measured in days, not hours, making their application to the emergency setting—where time is a factor—difficult.

Due to the potential for drug toxicity, using the same antiemetic drug repeatedly within a short amount of time in a patient refractory to therapy may not be the best strategy in the ED. It is most likely more beneficial and effective to switch drugs or use a combination of drugs right away—though this approach has theoretical concerns with drug-drug interactions. Again, this is an area in which further study is needed.

Treatment-Related Nausea and Vomiting

A recent review on breakthrough CINV again cited the paucity of clinical trials for this entity. Based on few studies, olanzapine and metoclopramide seem to be of value when prophylactic antiemetic regimens have failed. The review further noted that treatment of breakthrough CINV with an agent from same drug class as that used in the prophylactic regimen (usually 5-HT₃ and NK1 antagonists) is unlikely to be successful.³² This review also mentioned an interesting phase 2 study using a transdermal gel consisting of diphenhydramine, haloperidol, and lorazepam to the wrist, in which 27 of 33 patients in the study reported a decrease in nausea within a 4-hour period.³³ The same combination of drugs in IV form (lorazepam 0.5 mg, diphenhydramine 12.5 mg, and haloperidol 1 mg) is frequently used in the ED at the authors’ institution to treat breakthrough vomiting refractory to metoclopramide, antihistamines, or 5-HT₃ antagonists. To the authors’ knowledge, this combination treatment has not been previously cited in the medical literature.

Recommendations and Summary

Cancer patients presenting to the ED with nausea and vomiting should be thoroughly evaluated regarding the possible etiology of their symptoms. A careful history must include recent chemotherapy, radiation, medications, as well as knowledge of the potential complications associated with the specific type of cancer. The EP also should keep in mind that delayed nausea and vomiting can be present several days after chemotherapy, and that CINV may not manifest until after the initial prophylactic medications have worn off. Moreover, he or she should be aware that some individuals have unique responses to chemotherapy and radiation and may experience more nausea and vomiting symptoms than is considered typical.

In addition to CINV, other etiologies, including GI issues such as delayed gastric emptying, partial bowel obstruction, and constipation should also be carefully considered. When evaluating the patient, the EP should also consider non-GI causes such as elevated ICP, kidney obstruction, infection, silent cardiac ischemia, steroid withdrawal, Addisonian crisis, and electrolyte abnormalities.

The lack of conclusive evidence for the treatment of cancer-related nausea and vomiting in any circumstance—except for prophylaxis prior to chemotherapy—precludes the recommendation of a specific treatment algorithm. However, the evidence is abundant that there are multiple effective agents with different, if not overlapping, mechanisms of action available. The EP, therefore, should be familiar with the most commonly used antiemetic drugs from several different categories and their side effects, and tailor the approach based on the assumed etiology of the symptoms. When treating CINV or cancer-related nausea and vomiting, it is not uncommon that patients may require multiple agents, either simultaneously or in sequence, to obtain symptom resolution.

Dr Sandoval is an assistant professor, department of emergency medicine, division of internal medicine at The University of Texas MD Anderson Cancer Center, Houston. Dr Rice is an assistant professor and clinical medical director in the department of emergency medicine, division of internal medicine at The University of Texas MD Anderson Cancer Center, Houston.

Nausea and vomiting is common in cancer patients and a frequent presentation in the ED. When evaluating nausea and vomiting, the clinician should be aware that the two are not always linked—nausea may present without vomiting and vice versa. Nausea is “an unpleasant sensation of the need to vomit and is associated with autonomic symptoms,” whereas vomiting is “the forceful propulsion of abdominal contents via the contraction of the abdominal musculature and diaphragm.”¹ Whether these symptoms present together or independently of each other, both can result in serious metabolic disturbances, internal injury, malnutrition, and poor quality of life. In addition, nausea and vomiting can result in patient withdrawal from potentially beneficial treatment.² Based on the current literature, this article reviews and provides recommendations on appropriate assessment and treatment of the cancer patient presenting to the ED with nausea and/or vomiting.

Epidemiology

In 2007, the US Nationwide Emergency Department Sample database noted 122 million ED visits, 1.6 million of which were due to nausea and vomiting.³ In contrast, a small study from the United Kingdom cited 18% of ED visits in one of its centers were due to nausea and/or vomiting, demonstrating that the percentage of patients presenting with these symptoms can vary greatly.⁴

The incidence of cancer-related nausea and vomiting in the ED is unknown. Although EDs affiliated with large cancer centers see many cases of cancer-associated nausea and vomiting, presentations to noncancer-center EDs are becoming more prevalent due to increases in community-based cancer care.⁵ While the number of cancer patients is rising and the general population is aging,⁶ there is now less incidence of breakthrough chemotherapy-induced nausea and vomiting (CINV), which is a common cause of cancer-related nausea and vomiting. Older studies quote a 40% to 60% rate of breakthrough CINV; however, with the advent of newer antiemetic prophylaxis, by 2013 the incidence had decreased to about 28%.⁷ As such, the net effect may be a stable or decreased number of ED visits. In one study of patients with breakthrough CINV, 64% were treated inpatient, 26% outpatient, and 10% in the ED. The study, however, does not note how many of these inpatient visits originated in the ED, highlighting that this is an area in need of further study.⁸

Current knowledge about the epidemiology and etiology of non-CINV comes from end-of-life (EOL) palliative-care literature treatment guidelines, which are organized by cause (etiology-based antiemetic treatment [EBAT]).^9-11 Although one systematic review found that the EBAT approach “cannot be shown to be more effective than using a single antiemetic at effective doses,”¹² the etiologic framework is useful and can be applied to non-EOL patients. According to a systematic review on the prevalence of symptoms, nausea in advanced cancer patients ranged from 6% to 68%.⁶ Another review on cancer-related nausea and vomiting that cited studies conducted in the 1990s showed patients had increased nausea and vomiting as they approach EOL—ranging from 36% upon entering palliative-care programs to 71% in the final week of life.¹³ However, another systematic review citing more recent studies contradicts these findings, stating that in the last 2 weeks of life, nausea was less common (17%) than in patients who were not at the last 2 weeks of life (31%);¹⁴ the same was true of vomiting (20% vs 13%). This data perhaps implies that treatment of nausea and vomiting has improved over time for EOL patients. The same review also found that women were more likely to experience nausea and vomiting than men,¹⁴ a finding also seen in a 2011 prospective study of antiemetics for breakthrough CINV vomiting.¹⁵

When evaluating patients with cancer-associated nausea and vomiting, it is important to remember that these symptoms rarely occur in isolation. Most patients present with between seven and 15 other complaints, such as pain, weakness, fatigue, anorexia, constipation, dry mouth, early satiety, and dyspnea.¹⁶

Pathophysiology

To understand nausea and vomiting, it is helpful to review the emetic pathway. There are four areas that stimulate the central vomiting center located in the medulla oblongata. These are the cerebral cortex, the vestibular nucleus, the intestinal tract, and the chemoreceptor trigger zone (located on the floor of the fourth ventricle). With sufficient input from any of these to the vomiting center, nausea occurs, followed by the vomiting reflex. It is known that each of the input zones, as well as the vomiting center itself, have receptors for various substances, including the following:^1,13,17-20

·        Cerebral cortex: gamma-aminobutyric acid, histamine type 1 (H₁)

·        Vestibular nucleus: muscarinic acetylcholine receptor (AChM), H₁

·        Intestinal tract: 5 hydroxytryptamine type 3 (5-HT₃) or serotonin type 3 receptors, 5 hydroxytryptamine type 4 (5-HT₄) or serotonin type 3 receptors, dopamine type 2 (D2)

·        Chemoreceptor trigger zone: 5 hydroxytryptamine type 2 (5-HT₂) or serotonin type 2; D2, neurokinin-1 (NK1), or substance P

·        Vomiting center: AChM, H₁, 5-HT₂, D2, NK1, ([GK mµ] opioid receptors), and cannabinoid (CB) receptors

Each of the aforementioned substances in turn stimulate receptors in the intestinal tract and in the chemoreceptor trigger zone, triggering the vomiting center.^1,13,17 Most antiemetic agents block the receptors for one or more of these mediators and are discussed later in more detail. Chemotherapeutic agents specifically cause the release 5-HT and NK1 in the gut, which contains over 90% of the body’s serotonin. This knowledge has led to the development of newer 5-HT₃ and NK1 antagonists for CINV. Unlike the other mediators, cannabinoids cause an antiemetic effect when they bind to CB receptors.^13,17,19 This finding has led to the development of specific pharmacologic treatment agents. 

Etiology and Differential Diagnosis

Perhaps the best way for the emergency physician (EP) to assess the cancer patient with nausea or vomiting is to determine whether the cause is treatment- or nontreatment-related. Treatment-related causes are due to chemotherapy or radiotherapy, and any other causes would be considered nontreatment related. It is, however, wise for the EP to remember that a patient who has had recent chemotherapy can still be at risk for nontreatment etiologies.

Treatment-Related Nausea and Vomiting

Chemotherapy-Induced

Chemotherapy-induced nausea and vomiting has been well-studied in the literature. Chemotherapy is classified as highly, moderately, low, and minimally emetogenic.^18,19 Nausea itself is classified as acute (onset within 24 hours), delayed (onset after 24 hours), and anticipatory (prior to the chemotherapy, usually due to anxiety over previous unpleasant experiences). Breakthrough vomiting occurs despite the use of antiemetics and may be acute or delayed up to 5 days.

When evaluating the patient with recent chemotherapy and vomiting, it is prudent to find out if the agent is expected to cause vomiting. For example, a patient on cladribine, which is classified as minimally emetogenic, who experiences significant nausea and vomiting should likely be worked up for another etiology. Even when vomiting is controlled, a significant number of patients still experience nausea without vomiting, which in turn has a negative impact on quality of life.

Even though prophylactic regimens of 5-HT₃ and NK1 receptor antagonists have led to improved rates of CINV control,^18,19,21 both persistent nausea without vomiting and breakthrough vomiting remain problematic,¹⁸ and little scientific work has been done on breakthrough treatment. A small prospective pilot study of the efficacy of prochlorperazine versus serotonin 5-HT₃ receptor antagonists for breakthrough vomiting found both medications reduced nausea by 75% at 4 hours.¹⁵ In contrast, randomized controlled trials comparing olanzapine to metoclopramide and prochlorperazine for breakthrough vomiting found that at 3 days, olanzapine consistently achieved total relief of vomiting 66% to 70%, while the success rates of the other agents ranged from 20% to 37%.¹⁸

Radiotherapy-Induced

Radiotherapy has long been known to adversely affect the gastrointestinal (GI) tract. 5-HT₃ (ie, serotonin) is released from the gut enterochromaffin cells, in a manner similar to chemotherapy. A 2015 review on the subject showed that radiotherapy to the upper abdomen is most likely to lead to nausea and vomiting, with 50% to 67% of patients reporting nausea and 21% to 38% reporting vomiting.²⁰ Recommended prophylaxis and treatment regimens are based on consensus expert opinion, highlighting the lack of quality evidence that is seen with CINV. Prophylaxis regimens use 5-HT₃ antagonists prior to every session, plus dexamethasone for the first 5 days. Rescue from breakthrough is also treated with 5-HT₃ antagonists. The use of daily 5-HT₃ antagonists for a long course of radiotherapy, however, can be very expensive and unnecessary.

In addition, there is a delayed nausea and vomiting phenomena that may be due to substances other than serotonin, since 5-HT₃ depletes a few days after radiotherapy is begun, and may explain why 5-HT₃ antagonists are less effective after the first few days of radiotherapy. Nonpharmacologic treatments such as acupuncture, acupressure, hydrogen therapy, and ginger have been used or proposed as treatments for nausea, with mild benefit and little toxicity, so they should be studied further.²⁰

Nontreatment-Related Nausea or Vomiting

·        Impaired gastric emptying due to tumor or hepatomegaly, bowel obstruction, metabolic problems (eg, renal failure, liver failure, hypercalcemia, hyponatremia, ketoacidosis)

·        infection

·        drugs

·        increased intracranial pressure (ICP)

·        anxiety

The above causes of nausea and vomiting accounted for 85% of the cases in the study.⁹ Similar results were found in another study, showing that impaired gastric emptying and metabolic/drugs each caused about one third of the cases.¹⁰

Nontreatment-related causes of nausea and vomiting are traditionally divided into the following six broad etiological categories by palliative care practitioners^9,10,13:

1.  Biochemical: medications, tumor products, metabolic derangements, comorbidities, including systemic infections, noncancer abdominal illnesses; and silent cardiac ischemia

2.  Gastric stasis: tumor, neuropathy, hepatomegaly, ascites

3.  Bowel dysmotility/obstruction: tumor, metastases, adhesions, ileus, constipation

4.  Intracranial pressure: tumor edema, bleeding, hydrocephalus, leptomeningeal disease

5.  Vestibular: opioids, comorbid vestibular problems, brainstem metastases

6.  Miscellaneous: anxiety, pain

  These classification schemes are designed to help guide the treatment of palliative-care patients (EBAT),^9-11 but very little evidence supports the recommendations.^11-13,17 Expert opinion consensus guidelines favor haloperidol for biochemical etiology and metoclopramide for impaired gastric emptying. In intestinal obstruction, the H₁-blocking antihistamine cyclizine and the anticholinergic hyoscine butylbromide (scopoloamine) are the preferred agents, but dexamethasone and haloperidol are also favored by some. It is believed that increased ICP nausea is best treated with cyclizine and dexamethasone. Vestibular etiologies are treated with cyclizine, and anxiety-mediated nausea should be treated with benzodiazepines.^9,17 As there are often multiple etiologies in a given patient, selection of one agent can be problematic.¹³ Furthermore, no studies have applied these guidelines to ED cancer patients. This framework, however, can assist the EP in forming a differential diagnosis and appropriate workup. On history and physical examination, the EP should look for and consider the following:^13,16

·        Small-volume undigested emesis shortly after eating, suggesting gastric emptying impairment

·        Bilious or feculent vomitus, large volumes, constipation, and obstipation, suggesting bowel obstruction (evaluate via X-ray or computed tomographic imaging)

·        Early morning nausea and headache, suggesting increased ICP

·        Nausea associated with head movement or motion, with or without vertigo, (suggesting vestibular disease)

·        Current or recent use of opioids, antibiotics, antifungals, anticonvulsants, vitamins, ethanol, and selective serotonin reuptake inhibitors

·        Infection, sepsis

·        Metabolic abnormalities found on blood tests (for example, renal failure, liver failure, hypercalcemia, hyponatremia, ketoacidosis, osmolar gap, toxins/poisons, Addisonian crisis from steroid withdrawal or adrenal metastases); and/or

·        Silent cardiac ischemia (evaluate via electrocardiography and cardiac enzymes)

·        Careful consideration of each of the above possibilities will make one less likely to miss other serious causes of nausea and vomiting in the cancer patient with recent chemotherapy.

Opioid-Induced Nausea

Forty percent of cancer patients taking opioids experience nausea, which can adversely impact pain control.²² Opioid-induced nausea is due to constipation, gastroparesis, stimulation of the chemoreceptor trigger zone, and sensitization of the labyrinth, all of which can in turn stimulate the vomiting center.

Regarding the treatment of opioid-induced nausea and vomiting, there is no evidence to support the use of one antiemetic over another. Some weak evidence-based recommendations suggest either changing the medication to a different opioid, or changing the route of administration from oral to subcutaneous and adding coanalgesics such as gabapentin or ketamine to reduce opioid dosages. Though these strategies may be helpful in practice, none of the studies was large enough or thorough enough to support or warrant any formal recommendations in this systematic review.²²

Initial Management and Treatment

As always, attention to the patient’s airway, breathing, and circulation is of utmost importance. Endotracheal intubation should be considered in patients at risk for aspiration—unless a living will or do-not-resuscitate order exists. Maneuvers such as raising the head of the bed or turning the patient on his or her side may help avoid aspiration.

Intravenous (IV) hydration is generally beneficial. The choice and amount of fluid should be based on clinical judgment. Electrolyte imbalances should be corrected. The mainstay of treatment for nausea and/or vomiting is pharmacologic, which is the focus of the next section.

Pharmacologic Management

Prokinetic Agents

Prokinetic agents increase peristalsis and exert an antiemetic effect. Metoclopramide is the best known and most widely available prokinetic agent. Since it is both inexpensive and very effective as an antiemetic, its use in the ED is widespread. Etiology-based antiemetic treatment guidelines list metoclopramide as the antiemetic of choice when gastroparesis or other gastric emptying problems are diagnosed^9,10,13,17 as it exerts both D2 and 5-HT₃ central nervous system (CNS) antiemetic effects, relaxes pyloric tone (D2), and increases peristalsis by stimulating 5-HT₄ serotonin receptors in the gut.

The main limitation of metoclopramide is its extrapyramidal side effects (eg, akathisia, dystonia, psuedoparkinsonism, dyskinesia). Akathisias (ie, restlessness) is a particularly common phenomenon in patients taking metoclopramide. Patients experiencing extrapyramidal reactions are typically treated with diphenhydramine. In addition to the extrapyramidal side effects, metoclopramide is relatively contraindicated in patients with complete bowel obstruction.^13,17

In addition to metoclopramide, erythromycin and mirtazapine are other prokinetic agents used in palliative care. Erythromycin has mainly been used for diabetic gastroparesis due to its stimulatory effect on motilin receptors in the GI tract.^13,23 Mirtazapine is an antidepressant with both 5-HT₃ and 5-HT₄ receptor activity. In one case report it was used to treat gastroparesis refractory to all other therapies, including metoclopramide and erythromycin.²³

Dopamine-Receptor Antagonists

This category includes many agents, most which are known for their antipsychotic effects. The primary mode of action of dopamine-receptor antagonists is to block D2 receptors in the vomiting center. Etiology-based antiemetic treatment guidelines list these drugs as the first choice in patients with a biochemical-based etiology for nausea, though there is little-to-no evidence to support this recommendation.^{9,10,12,13,17}

While a review on haloperidol use in cancer found its effects better than placebo for CINV and postoperative nausea, studies in the review were small and the evidence weak.²⁴ Due to its low cost, and comparatively favorable side-effect profile, haloperidol is a reasonable alternative to metoclopramide. Indeed, if palliative-care models are used, haloperidol would be preferred over metoclopramide since biochemical nausea is probably more prevalent in the general ED cancer patient than gastroparesis.

Regarding route of administration, olanzapine can be given orally or intramuscularly, making it potentially useful in the ED setting for those who cannot keep pills down and have poor venous access. When used in the supportive care setting, however, olanzapine is typically given at bedtime due to its sedative effects. As such, this agent may be best given to those who will be admitted or placed on observation status, since some patients may not be able to be discharged even if nausea resolves.

Antihistamine Agents

Cyclizine, diphenhydramine, hydroxyzine, meclozine, and promethazine, are all piperazine H₁-receptor blockers that work in the vomiting center, vestibular nucleus, and chemoreceptor trigger zone. In addition to its properties as an H₁-receptor antagonist, cyclizine also exhibits some anticholinergic activity that decreases bowel secretions, thus making it theoretically beneficial in patients with bowel obstruction. Each of these antihistamines are considered beneficial in treating nausea due to vestibular dysfunction and in motion sickness, and may be helpful in patients with increased ICP. Heavy sedation, anticholinergic, and extrapyramidal side effects may occur with these drugs, especially in elderly patients.^1,13,17

Serotonin 5-HT3 Receptor Antagonists

Dolasetron, granisetron, ondansetron, palonosetron, and tropisetron are among the 5-HT₃ (serotonin type 3) receptor antagonists used to treat nausea and vomiting. As previously stated, chemotherapy stimulates release of 5-HT from the gut, which in turn stimulates 5-HT₃ receptors in the gut, vagus nerve, and the chemotherapy trigger zone—all of which in turn stimulate the vomiting center, leading to the vomiting reflex.^{1,13,17,19,21} The blocking action of these drugs on the 5-HT₃ receptors is the basis of the antiemetic effect. Palonosetron, with its long 40-hour half-life, has become the preferred prophylactic agent for CINV. The most common adverse events with 5-HT₃ antagonists include mild headache, transient elevation of hepatic aminotransferase levels, and constipation.^19,21 The use of ondansetron for emesis in the ED is becoming more established both for CINV and non-CINV—mainly due to its high efficacy and favorable side-effect profile compared to metoclopramide and the dopamine antagonists.

Substance P Antagonists (NK1-Receptor Antagonists)

Oral aprepitant, injectable fosaprepitant, and netupitant are some of the Substance P (NK1) antagonists used to treat nausea and vomiting. In a manner similar to 5-HT release, chemotherapeutic agents stimulate the cellular release of NK1 in the gut. This reaction in turn activates receptors in the vagus nerve and the chemotherapy trigger zone, which stimulates the vomiting center. The NK1 receptors are blocked by these agents. The main use of these medications has been to complement the 5-HT₃ antagonists for prophylaxis prior to administration of chemotherapy. Neurokinin-1receptor antagonists have not been studied in the setting of breakthrough nausea and vomiting but they are being used to treat delayed phase breakthrough CINV by the authors at their institution’s ED.  The agents  have been shown to be more effective than 5-HT₃ agents in preventing delayed phase nausea and vomiting.²⁵ As such, the possibility they may also be effective in treating delayed phase breakthrough CINV has led to this use. Recent studies have found these agents highly effective in the treatment of postoperative nausea and vomiting in high-risk patients.²⁶ 

The standard in recent years for prophylaxis has been combining 5-HT₃ antagonists, NK1 inhibitors, and dexamethasone. Netupitant/palonosetron (commonly referred to as NEPA) is a novel oral agent combining a long-acting 5-HT₃ antagonist, and a long-acting NK1 inhibitor for CINV prophylaxis.²⁷ Its use in treating delayed breakthrough vomiting remains to be seen.

Corticosteroids

Based on its antiemetic properties, the corticosteroid dexamethasone increases the effects of antiemetics (ie, metoclopramide and more recently 5-HT₃ and NK1 receptor antagonists) in preventing CINV, perhaps by reducing the blood-brain barrier permeability to emetogenic substances. There are also some evidence-based benefits in using dexamethasone in patients with bowel obstruction. It is also used to reduce ICP from cerebral edema.^{1,11,13,17,19}

Benzodiazepines

The benzodiazepines are best given to enhance the antiemetic effects of other drugs, especially in patients experiencing anxiety-related side effects. The benzodiazepines work well for anticipatory nausea. Lorazepam is the preferred drug of choice due to the lack of active metabolites. However, the clinician should always exercise caution when using benzodiazepines in elderly patients due to the increased risk of falls and cognitive impairment.^13,17,19

Cannabinoids

The observation that the incidence of CINV decreased in marijuana smokers led to the exploration of cannabinoids for the treatment of nausea and vomiting. Tetrahydrocannabinol, the psychoactive substance in marijuana, is a phytocannabinoid. Its receptor, CB1, exists throughout the brain. Synthetic cannabinoids such as oral dronabinol, oral nabilone, and intramuscular levonantradol have been used with antiemetic success superior to chlorpromazine, haloperidol, metoclopramide, and prochlorperazine, but at the cost of unpleasant CNS effects and postural hypotension in elderly patients.^1,13,17

As cited in a systematic review, cannabinoids appear to inhibit growth of glioblastoma multiforme, breast, prostate, and thyroid cancer, colon carcinoma, leukemia, and lymphomas. Cannabinoids can also benefit cancer patients by stimulating appetite, elevating mood, and inhibiting pain.²⁸ Clearly, more oncologic research needs to be done on the topic. As such, this class of medication is years, if not decades, away from use in the ED.

Nonpharmacologic Treatments

Acupuncture and Acupressure

A 2006 Cochrane systematic review and meta-analysis showed that acupuncture helped with acute CINV but not with delayed CINV.²⁹ Acupuncture was shown to work best with electro-acupuncture needles. Acupressure without needles helped nausea but not vomiting.²⁹ A more recent review on the specific P6 acupuncture area on the wrist near the median nerve found that electroacupuncture, but not manual acupuncture, was beneficial for first-day vomiting, and acupressure was effective for first-day nausea but not vomiting. Neither acupuncture nor acupressure was shown to help delayed nausea or vomiting.³⁰

Ginger

Ginger has been shown to help with CINV and anticipatory nausea, but not with other types of nausea.¹³ Supplementing routine antiemetics with 0.5 to 1.5 g of ginger per day for 6 days (beginning 3 days before chemotherapy) was shown to reduce the severity of nausea on the day of chemotherapy, but did not affect vomiting.²¹

Percutaneous Gastrostomy, Stenting, and Laser Therapy

Several strategies have been developed for palliation of intestinal obstruction when surgery is not warranted. Percutaneous gastrostomy tubes (PEG) are used to vent GI secretions that would otherwise build up. Esophageal, colorectal, and gastric outlet obstructions can be palliated by endoscopically placed stenting devices. Argon beam plasma coagulation laser therapy can be used for gastric outlet as well as colonic obstruction.^13,31 One review evaluating the benefits of colonic obstruction stenting found an 89% success rate in symptom relief. This same review noted that venting the PEG tube placement had an 84% rate of symptom relief.³¹

Selecting an Agent in the ED: the Evidence (or Lack Thereof)

Nontreatment-Related Nausea and Vomiting

A 2011 systematic review of cancer nausea unrelated to chemotherapy or radiotherapy found level B evidence that metoclopramide is the most effective first-line empiric agent. In patients with bowel obstruction, dexamethasone, hyoscine butylbromide (scopolamine), and octreotide are effective. While dexamethasone is often thought to improve the effects of antiemetic drugs, this review showed it did not improve nausea when added to chlorpromazine or metoclopramide. Furthermore, neither metoclopramide nor ondansetron were shown to reduce opioid-induced emesis.¹³ The review further pointed out the lack of good evidence for expert opinion guideline recommendations in breakthrough vomiting—eg, dose titration of the same drug, switching to a different drug class, or using two or more drugs together at once.¹³

Another review had similar findings, while pointing out that an “absence of evidence is not evidence of absence,” and noting that many of these treatments have been used for years—ie, the problem is lack of evidence, but not negative evidence.¹⁷ Both studies are notable in that they were all done in palliative-care units in which time to relief from nausea and/or vomiting was typically measured in days, not hours, making their application to the emergency setting—where time is a factor—difficult.

Due to the potential for drug toxicity, using the same antiemetic drug repeatedly within a short amount of time in a patient refractory to therapy may not be the best strategy in the ED. It is most likely more beneficial and effective to switch drugs or use a combination of drugs right away—though this approach has theoretical concerns with drug-drug interactions. Again, this is an area in which further study is needed.

Treatment-Related Nausea and Vomiting

A recent review on breakthrough CINV again cited the paucity of clinical trials for this entity. Based on few studies, olanzapine and metoclopramide seem to be of value when prophylactic antiemetic regimens have failed. The review further noted that treatment of breakthrough CINV with an agent from same drug class as that used in the prophylactic regimen (usually 5-HT₃ and NK1 antagonists) is unlikely to be successful.³² This review also mentioned an interesting phase 2 study using a transdermal gel consisting of diphenhydramine, haloperidol, and lorazepam to the wrist, in which 27 of 33 patients in the study reported a decrease in nausea within a 4-hour period.³³ The same combination of drugs in IV form (lorazepam 0.5 mg, diphenhydramine 12.5 mg, and haloperidol 1 mg) is frequently used in the ED at the authors’ institution to treat breakthrough vomiting refractory to metoclopramide, antihistamines, or 5-HT₃ antagonists. To the authors’ knowledge, this combination treatment has not been previously cited in the medical literature.

Recommendations and Summary

Cancer patients presenting to the ED with nausea and vomiting should be thoroughly evaluated regarding the possible etiology of their symptoms. A careful history must include recent chemotherapy, radiation, medications, as well as knowledge of the potential complications associated with the specific type of cancer. The EP also should keep in mind that delayed nausea and vomiting can be present several days after chemotherapy, and that CINV may not manifest until after the initial prophylactic medications have worn off. Moreover, he or she should be aware that some individuals have unique responses to chemotherapy and radiation and may experience more nausea and vomiting symptoms than is considered typical.

In addition to CINV, other etiologies, including GI issues such as delayed gastric emptying, partial bowel obstruction, and constipation should also be carefully considered. When evaluating the patient, the EP should also consider non-GI causes such as elevated ICP, kidney obstruction, infection, silent cardiac ischemia, steroid withdrawal, Addisonian crisis, and electrolyte abnormalities.

The lack of conclusive evidence for the treatment of cancer-related nausea and vomiting in any circumstance—except for prophylaxis prior to chemotherapy—precludes the recommendation of a specific treatment algorithm. However, the evidence is abundant that there are multiple effective agents with different, if not overlapping, mechanisms of action available. The EP, therefore, should be familiar with the most commonly used antiemetic drugs from several different categories and their side effects, and tailor the approach based on the assumed etiology of the symptoms. When treating CINV or cancer-related nausea and vomiting, it is not uncommon that patients may require multiple agents, either simultaneously or in sequence, to obtain symptom resolution.

Dr Sandoval is an assistant professor, department of emergency medicine, division of internal medicine at The University of Texas MD Anderson Cancer Center, Houston. Dr Rice is an assistant professor and clinical medical director in the department of emergency medicine, division of internal medicine at The University of Texas MD Anderson Cancer Center, Houston.

Case

A 36-year-old woman with a 2-week history of left flank pain presented to the ED via emergency medical services. The patient, who had a history of nephrolithiasis, assumed her pain was due to another kidney stone. She stated that while waiting for the presumed stone to pass, the pain in her left flank worsened and she felt lightheaded and weak.

The patient’s vital signs at presentation were: heart rate, 96 beats/minute; blood pressure, 133/76 mm Hg; respiratory rate, 20 breaths/minute; and temperature, 98.9˚F. Oxygen saturation was 98% on room air. On physical examination, the patient had left lower quadrant pain and left costovertebral angle tenderness. Laboratory studies were remarkable for a negative urine pregnancy test, a hemoglobin level of 6.8 g/dL, and a hematocrit of 21.1%. Based on the patient’s history and symptoms, axial and coronal computed tomography (CT) scans were ordered, revealing a ruptured left renal calyx with hemorrhage from ureterolithiasis (Figures 1a and 1b).

Rupture of renal calyx and extravasation of blood or urine is a potential complication of nephrolithiasis. Stone size, degree of obstruction, and length of symptomatic presentation presumably contribute to complications from nephrolithiasis. Stones that are symptomatic for more than 4 weeks are estimated to have an increased complication rate of up to 20%.¹

Calyx or fornix rupture results from increased intraluminal pressure. Rupture of these structures is thought to be a type of “safety-valve” function to relieve obstructive uropathy.²

Obstructions from small leaks to large urinomas can cause extravasation of urine. In most cases, urinary extravasation is confined to the subcapsular space or perirenal space within the Gerota’s fascia;³ however, as seen in this patient, mixed hematoma/urinomas can form.

Causes

In cases of nontraumatic calyx rupture, the cause of the obstruction is most often a distal obstructing ureteral stone.⁴ Other causes of rupture include extrinsic compression from malignant and benign masses, ureteric junction obstructions, or iatrogenic causes.⁴ Interestingly, in one small study, the median size of the obstructing stone was only 4 mm. The same study also noted that proximal ureteral obstruction occurred when larger stones where present.⁴

Conservative Versus Nonconservative Management

Potential complications of urinomas include abscess formation, sepsis, hydronephrosis, and paralytic ileus.³ Despite possible adverse sequelae, uncomplicated urinomas may be managed conservatively with supportive care. According to a study by Chapman et al,⁵ about 40% of patients managed conservatively recover without complications. In addition, in a retrospective study by Doehn et al⁶ involving 160 cases of fornix rupture treated with endoscopic therapy or nephrostomy tube supplemented with antibiotics, no instances of perinephric abscess or other complications requiring a second procedure were noted.

Management of suspected ureterolithiasis in the ED is focused on analgesia and supportive care. Acute analgesia is often provided parenterally with opioids alone or with an opioid/nonsteroidal anti-inflammatory drug (NSAID) combination.⁷ Frequent reassessment of the patient is required to ensure adequate pain control and to prevent sedation. Other symptoms, such as nausea, vomiting, and dehydration, may be treated with intravenous (IV) fluids and antiemetic medications. Further radiographic evaluation is needed once analgesia is achieved.^7,8

Imaging Studies

Radiological evaluation of patients with suspected ureterolithiasis may involve several imaging modalities. Noncontrast helical CT scan is the standard for rapid and efficient identification of ureteral stones while allowing visualization of other potential pathology (eg, urinoma).^7-9 Other modalities, such as ultrasonography; radiography of the kidneys, ureters, and bladder; and an IV pyelogram with contrasted CT, may be ordered if noncontrast helical CT scan is not available on-site or if there are comorbidities. In addition to imaging studies, basic laboratory studies (eg, serum creatinine and blood urea nitrogen testing) are indicated to assess overall renal function and direct the choice of radiological study.⁷

Disposition

Clinical decision-making is key when recommending inpatient versus outpatient treatment in patients with ureterolithiasis. Patients with uncontrolled pain or vomiting may require inpatient admission for supportive care, while those demonstrating acute renal failure, pyuria with bacteriuria, complete bilateral ureteral obstruction, urinoma, or signs of sepsis demand emergent urology consultation. Specifically, patients with urinoma require ureteroscopy versus nephrostomy^6,10 to allow drainage while carefully monitoring for development of subsequent bleeding and infection.

When discharging patients from the ED, expulsive therapy using tamsulosin⁹ and analgesia with combination of oral opioids and NSAIDs are most commonly effective.¹¹ Outpatient urology referrals are recommended for ureteral stones greater than 5 mm in size or if the stones have been present in the ureter for greater than 4 weeks.¹ Proper evaluation and management of ureterolithiasis in the ED is crucial for positive outcomes and to reduce long-term complications.

Case Conclusion

Computed tomography revealed a ruptured renal calyx on the left side with free fluid in the abdomen. Urology services were consulted and the patient was taken to the operating room for cystoscopy, ureteral stent placement, and laser lithotripsy. Following surgery, she subsequently developed urosepsis for which she was successfully treated with IV antibiotics and discharged on hospital day 15.

Mr Eisenstat is a fourth-year medical student at the University of South Carolina School of Medicine, Greenville. Dr Fabiano is an emergency physician, department of emergency medicine, Greenville Health Systems, Greenville, South Carolina. Dr Collins is family medicine physician, department of emergency medicine, Greenville Health Systems, Greenville, South Carolina.

Case

A 36-year-old woman with a 2-week history of left flank pain presented to the ED via emergency medical services. The patient, who had a history of nephrolithiasis, assumed her pain was due to another kidney stone. She stated that while waiting for the presumed stone to pass, the pain in her left flank worsened and she felt lightheaded and weak.

The patient’s vital signs at presentation were: heart rate, 96 beats/minute; blood pressure, 133/76 mm Hg; respiratory rate, 20 breaths/minute; and temperature, 98.9˚F. Oxygen saturation was 98% on room air. On physical examination, the patient had left lower quadrant pain and left costovertebral angle tenderness. Laboratory studies were remarkable for a negative urine pregnancy test, a hemoglobin level of 6.8 g/dL, and a hematocrit of 21.1%. Based on the patient’s history and symptoms, axial and coronal computed tomography (CT) scans were ordered, revealing a ruptured left renal calyx with hemorrhage from ureterolithiasis (Figures 1a and 1b).

Rupture of renal calyx and extravasation of blood or urine is a potential complication of nephrolithiasis. Stone size, degree of obstruction, and length of symptomatic presentation presumably contribute to complications from nephrolithiasis. Stones that are symptomatic for more than 4 weeks are estimated to have an increased complication rate of up to 20%.¹

Calyx or fornix rupture results from increased intraluminal pressure. Rupture of these structures is thought to be a type of “safety-valve” function to relieve obstructive uropathy.²

Obstructions from small leaks to large urinomas can cause extravasation of urine. In most cases, urinary extravasation is confined to the subcapsular space or perirenal space within the Gerota’s fascia;³ however, as seen in this patient, mixed hematoma/urinomas can form.

Causes

In cases of nontraumatic calyx rupture, the cause of the obstruction is most often a distal obstructing ureteral stone.⁴ Other causes of rupture include extrinsic compression from malignant and benign masses, ureteric junction obstructions, or iatrogenic causes.⁴ Interestingly, in one small study, the median size of the obstructing stone was only 4 mm. The same study also noted that proximal ureteral obstruction occurred when larger stones where present.⁴

Conservative Versus Nonconservative Management

Potential complications of urinomas include abscess formation, sepsis, hydronephrosis, and paralytic ileus.³ Despite possible adverse sequelae, uncomplicated urinomas may be managed conservatively with supportive care. According to a study by Chapman et al,⁵ about 40% of patients managed conservatively recover without complications. In addition, in a retrospective study by Doehn et al⁶ involving 160 cases of fornix rupture treated with endoscopic therapy or nephrostomy tube supplemented with antibiotics, no instances of perinephric abscess or other complications requiring a second procedure were noted.

Management of suspected ureterolithiasis in the ED is focused on analgesia and supportive care. Acute analgesia is often provided parenterally with opioids alone or with an opioid/nonsteroidal anti-inflammatory drug (NSAID) combination.⁷ Frequent reassessment of the patient is required to ensure adequate pain control and to prevent sedation. Other symptoms, such as nausea, vomiting, and dehydration, may be treated with intravenous (IV) fluids and antiemetic medications. Further radiographic evaluation is needed once analgesia is achieved.^7,8

Imaging Studies

Radiological evaluation of patients with suspected ureterolithiasis may involve several imaging modalities. Noncontrast helical CT scan is the standard for rapid and efficient identification of ureteral stones while allowing visualization of other potential pathology (eg, urinoma).^7-9 Other modalities, such as ultrasonography; radiography of the kidneys, ureters, and bladder; and an IV pyelogram with contrasted CT, may be ordered if noncontrast helical CT scan is not available on-site or if there are comorbidities. In addition to imaging studies, basic laboratory studies (eg, serum creatinine and blood urea nitrogen testing) are indicated to assess overall renal function and direct the choice of radiological study.⁷

Disposition

Clinical decision-making is key when recommending inpatient versus outpatient treatment in patients with ureterolithiasis. Patients with uncontrolled pain or vomiting may require inpatient admission for supportive care, while those demonstrating acute renal failure, pyuria with bacteriuria, complete bilateral ureteral obstruction, urinoma, or signs of sepsis demand emergent urology consultation. Specifically, patients with urinoma require ureteroscopy versus nephrostomy^6,10 to allow drainage while carefully monitoring for development of subsequent bleeding and infection.

When discharging patients from the ED, expulsive therapy using tamsulosin⁹ and analgesia with combination of oral opioids and NSAIDs are most commonly effective.¹¹ Outpatient urology referrals are recommended for ureteral stones greater than 5 mm in size or if the stones have been present in the ureter for greater than 4 weeks.¹ Proper evaluation and management of ureterolithiasis in the ED is crucial for positive outcomes and to reduce long-term complications.

Case Conclusion

Computed tomography revealed a ruptured renal calyx on the left side with free fluid in the abdomen. Urology services were consulted and the patient was taken to the operating room for cystoscopy, ureteral stent placement, and laser lithotripsy. Following surgery, she subsequently developed urosepsis for which she was successfully treated with IV antibiotics and discharged on hospital day 15.

Mr Eisenstat is a fourth-year medical student at the University of South Carolina School of Medicine, Greenville. Dr Fabiano is an emergency physician, department of emergency medicine, Greenville Health Systems, Greenville, South Carolina. Dr Collins is family medicine physician, department of emergency medicine, Greenville Health Systems, Greenville, South Carolina.

Case

A 36-year-old woman with a 2-week history of left flank pain presented to the ED via emergency medical services. The patient, who had a history of nephrolithiasis, assumed her pain was due to another kidney stone. She stated that while waiting for the presumed stone to pass, the pain in her left flank worsened and she felt lightheaded and weak.

The patient’s vital signs at presentation were: heart rate, 96 beats/minute; blood pressure, 133/76 mm Hg; respiratory rate, 20 breaths/minute; and temperature, 98.9˚F. Oxygen saturation was 98% on room air. On physical examination, the patient had left lower quadrant pain and left costovertebral angle tenderness. Laboratory studies were remarkable for a negative urine pregnancy test, a hemoglobin level of 6.8 g/dL, and a hematocrit of 21.1%. Based on the patient’s history and symptoms, axial and coronal computed tomography (CT) scans were ordered, revealing a ruptured left renal calyx with hemorrhage from ureterolithiasis (Figures 1a and 1b).

Rupture of renal calyx and extravasation of blood or urine is a potential complication of nephrolithiasis. Stone size, degree of obstruction, and length of symptomatic presentation presumably contribute to complications from nephrolithiasis. Stones that are symptomatic for more than 4 weeks are estimated to have an increased complication rate of up to 20%.¹

Calyx or fornix rupture results from increased intraluminal pressure. Rupture of these structures is thought to be a type of “safety-valve” function to relieve obstructive uropathy.²

Obstructions from small leaks to large urinomas can cause extravasation of urine. In most cases, urinary extravasation is confined to the subcapsular space or perirenal space within the Gerota’s fascia;³ however, as seen in this patient, mixed hematoma/urinomas can form.

Causes

In cases of nontraumatic calyx rupture, the cause of the obstruction is most often a distal obstructing ureteral stone.⁴ Other causes of rupture include extrinsic compression from malignant and benign masses, ureteric junction obstructions, or iatrogenic causes.⁴ Interestingly, in one small study, the median size of the obstructing stone was only 4 mm. The same study also noted that proximal ureteral obstruction occurred when larger stones where present.⁴

Conservative Versus Nonconservative Management

Potential complications of urinomas include abscess formation, sepsis, hydronephrosis, and paralytic ileus.³ Despite possible adverse sequelae, uncomplicated urinomas may be managed conservatively with supportive care. According to a study by Chapman et al,⁵ about 40% of patients managed conservatively recover without complications. In addition, in a retrospective study by Doehn et al⁶ involving 160 cases of fornix rupture treated with endoscopic therapy or nephrostomy tube supplemented with antibiotics, no instances of perinephric abscess or other complications requiring a second procedure were noted.

Management of suspected ureterolithiasis in the ED is focused on analgesia and supportive care. Acute analgesia is often provided parenterally with opioids alone or with an opioid/nonsteroidal anti-inflammatory drug (NSAID) combination.⁷ Frequent reassessment of the patient is required to ensure adequate pain control and to prevent sedation. Other symptoms, such as nausea, vomiting, and dehydration, may be treated with intravenous (IV) fluids and antiemetic medications. Further radiographic evaluation is needed once analgesia is achieved.^7,8

Imaging Studies

Radiological evaluation of patients with suspected ureterolithiasis may involve several imaging modalities. Noncontrast helical CT scan is the standard for rapid and efficient identification of ureteral stones while allowing visualization of other potential pathology (eg, urinoma).^7-9 Other modalities, such as ultrasonography; radiography of the kidneys, ureters, and bladder; and an IV pyelogram with contrasted CT, may be ordered if noncontrast helical CT scan is not available on-site or if there are comorbidities. In addition to imaging studies, basic laboratory studies (eg, serum creatinine and blood urea nitrogen testing) are indicated to assess overall renal function and direct the choice of radiological study.⁷

Disposition

Clinical decision-making is key when recommending inpatient versus outpatient treatment in patients with ureterolithiasis. Patients with uncontrolled pain or vomiting may require inpatient admission for supportive care, while those demonstrating acute renal failure, pyuria with bacteriuria, complete bilateral ureteral obstruction, urinoma, or signs of sepsis demand emergent urology consultation. Specifically, patients with urinoma require ureteroscopy versus nephrostomy^6,10 to allow drainage while carefully monitoring for development of subsequent bleeding and infection.

When discharging patients from the ED, expulsive therapy using tamsulosin⁹ and analgesia with combination of oral opioids and NSAIDs are most commonly effective.¹¹ Outpatient urology referrals are recommended for ureteral stones greater than 5 mm in size or if the stones have been present in the ureter for greater than 4 weeks.¹ Proper evaluation and management of ureterolithiasis in the ED is crucial for positive outcomes and to reduce long-term complications.

Case Conclusion

Computed tomography revealed a ruptured renal calyx on the left side with free fluid in the abdomen. Urology services were consulted and the patient was taken to the operating room for cystoscopy, ureteral stent placement, and laser lithotripsy. Following surgery, she subsequently developed urosepsis for which she was successfully treated with IV antibiotics and discharged on hospital day 15.

Mr Eisenstat is a fourth-year medical student at the University of South Carolina School of Medicine, Greenville. Dr Fabiano is an emergency physician, department of emergency medicine, Greenville Health Systems, Greenville, South Carolina. Dr Collins is family medicine physician, department of emergency medicine, Greenville Health Systems, Greenville, South Carolina.

Case Miscarriage in a 29-year-old woman
A woman (G0P0) presents to her gynecologist with amenorrhea for 3 months and a positive home urine pregnancy test. She is 29 years of age. She denies any bleeding or pain and intends to continue the pregnancy, though it was unplanned. Results of office ultrasonography to assess fetal viability reveal an intrauterine gestation with an 8-mm fetal pole but no heartbeat. The diagnosis is miscarriage.

This case illustrates a typical miscarriage diagnosis; most women with miscarriage are asymptomatic and without serious bleeding requiring emergency 
intervention. The management options include surgical, medical, and expectant. Women should be offered all 3 of these, and clinicians should explain the risks and benefits of each approach. But while each strategy can be safe, effective, and acceptable, many women, as well as their health care providers, will benefit from office-based uterine aspiration. In this article, we present the data available on office-based manual vacuum aspiration (MVA) as well as procedure pointers and urge you to consider MVA in your practice for your patients.

Surgical management
Surgical management of miscarriage offers several clear advantages over medical and expectant management. Perhaps the most important advantage to patients is that surgery offers rapid resolution of miscarriage with the shortest duration of bleeding.^1,2 When skilled providers perform electric vacuum aspiration (EVA) or MVA in outpatient or emergency department settings, successful uterine evacuation is completed in a single medical encounter 99% of the time.¹ By comparison, several follow-up visits and additional ultrasounds may be required during medical or expectant management. Uterine aspiration rarely requires an operating room (OR). Such a setting should be limited to cases in which the clinical picture reflects:

Office-based MVA
Office-based MVA is well tolerated when performed using a combination of verbal distraction and reassurance, oral nonsteroidal anti-inflammatory drugs (NSAIDs), and a paracervical block with or without intravenous sedation.

Evidence on managing pain at MVA. Multiple studies have assessed preprocedure and postprocedure pain using NSAIDs, oral anxiolytics, and local anesthesia at the time of EVA or MVA.^3,4 Renner and colleagues found that women who received a paracervical block prior to MVA or EVA reported moderate levels of pain, according to a 100-point visual analogue scale (VAS), at the time of cervical dilation (mean, 42) and uterine aspiration (mean, 63).⁴ In this same study, patients’ willingness to treat a future pregnancy with EVA or MVA using local anesthesia and their overall satisfaction with the procedure was high (mean, 90 on 100-point VAS).

In-office advantages over the OR. Women and clinicians can avoid the extensive scheduling delays associated with ORs, as well as the complications associated with medical and expectant management, if office-based EVA and MVA services are readily available. Compared with surgical management of miscarriage in an OR, office-based EVA and MVA are faster to complete. For example, Dalton and colleagues compared patients undergoing first-trimester procedures in an office setting with those undergoing a procedure in an OR. The mean procedure time for women treated in an office was 10 minutes, compared with 19 minutes for women treated in the OR. In addition, women 
treated in an office setting spent a mean total of 97 minutes at the office; women treated in an OR spent a mean total of 290 minutes at the hospital.⁵

Patients’ satisfaction with care provided in the OR was comparable to patients’ satisfaction with care provided in a medical office. In fact, the median total satisfaction score was high among women who had a procedure in either setting (office score, 19 of 20; OR score, 20 of 20).

Cost and equipment for in-office MVA
Office-based surgical management of miscarriage is more cost-effective than OR-based management. In 2006, Dalton and colleagues conducted a cost analysis and found that average charges for office-based MVA were less than half the cost of charges for a dilation and curettage (D&C) in the OR ($968 vs $1,965, respectively).⁵

More recently, these researchers found that usual care (expectant or OR management) was more costly than a model that also included medical and office-based surgical options. They found that the expanded care model—with use of the OR only when needed—cost $1,033.29 per case. This was compared with $1,247.58 per case when management options did not include medical and office-based surgical treatments.⁶

The cost of supplies needed to initiate MVA services within an established outpatient gynecologist’s office is modest. Equipment includes manual vacuum aspirators; disposable cannulae of various sizes; reusable plastic or metal dilators; supplies for disinfection, allowing reuse of MVA aspirators; and supplies for examination of products of conception (POC; FIGURE 1).

According to WomanCare Global, manufacturer of the IPAS MVA Plus, equipment should be sterilized after each use with soap and water, medical cleaning solution (such as Cidex, SPOROX II, etc.), or autoclaving.⁷ If 2 reusable aspirators are purchased along with dilators, disposable cannulae, and tools for tissue assessment, the price of supplies is estimated at US $500.⁸ WomanCare Global also offers prepackaged, single-use aspirator kits, which may be ideal for the emergency department setting.⁹

The procedure
To view a video on the MVA device and procedure, including step-by-step technique (FIGURE 2), local anesthesia administration, choosing cannula size, and cervical dilation, visit the Managing Early Pregnancy Loss Web site (http://www.earlypregnancylossresources.org) and access “Videos.” The video “Uterine aspiration for EPL” is available under password protection and broken into chapters for viewing ease.

The risk of endometritis after surgical management of miscarriage is low. Antibiotic prophylaxis prior to MVA or EVA should be considered. Experts recommend giving a single dose of doxycycline 200 mg orally at least 1 hour prior to uterine aspiration.^2,10

Use of EVA or MVA for outpatient management of miscarriage yields the opportunity to conduct immediate gross examination of the evacuated tissue and to verify the presence of complete POC. The process is simple: rinse the specimen through a sieve with water or saline, placed in a clear glass container under a small water bath and backlit on a light box. This allows clinicians to separate uterine decidua and pregnancy tissues. “Floating” tissue in this manner is especially useful in patients with pregnancy of unknown location, as immediate confirmation of a gestational sac rules out ectopic pregnancy.

Examine evacuated tissue for macroscopic evidence of pregnancy. Chorionic villi, which arise from syncytiotrophoblasts, can be seen with the naked eye. Immediate evaluation of POC is also useful for patients who desire diagnostic testing to ascertain a cause of their miscarriage because evacuated tissue stored in saline may be sent to a laboratory for cytogenetic analysis.

Medical management
Management of miscarriage with misoprostol is also safe and acceptable to women, though it has a lower success rate than surgical management.

Comparing efficacy: Medical vs surgical management. The Management of Early Pregnancy Failure Trial (MEPF) is the largest randomized controlled trial comparing medical management of miscarriage to surgical management. This multicenter study compared treatment with office-based EVA or MVA to vaginal misoprostol 800 µg. A repeat dose of vaginal misoprostol was offered 48 hours after the initial dose if a gestational sac was present on ultrasound.

Findings from the MEPF trial revealed a 71% complete uterine evacuation rate after 
1 dose of misoprostol and an 84% rate after 
2 doses.¹ The average (SD) reported pain score documented within 48 hours of treatment with misoprostol or MVA/EVA was moderate (5.7 cm [2.4] on 10-cm VAS). The rate of infection or hospitalization was less than 1% in both treatment groups.

These data should provide patients who are clinically stable and who wish to avoid an invasive procedure reassurance that using medication for the management of miscarriage is a reasonable option.

Misoprostol. Use of misoprostol is associated with a longer median duration of bleeding compared with suction aspiration. After misoprostol, bleeding usually begins after several hours and may continue for weeks.¹¹ Based on 2-week prospective bleeding diary entries from the MEPF trial, women who used misoprostol for management of miscarriage were more likely to have any bleeding during the 2 weeks after initiation of treatment, compared with women who had suction aspiration.¹²

Clinically significant changes in hemoglobin levels are more common in women treated with misoprostol than in those who choose EVA or MVA; however, these differences rarely require hospitalization or transfusion.¹ Women who are considering use of misoprostol should be aware of common adverse effects, including nausea, vomiting, diarrhea, and low-grade temperature.

Medical management of miscarriage requires multiple office visits with repeat ultrasounds or serum beta–human chorionic gonadotropin (β-hCG) levels to confirm treatment success. In cases of medication failure (persistent gestational sac with or without bleeding) or suspected retained POC (endometrial stripe greater than 
30 mm measured on ultrasound or persistent vaginal bleeding remote from treatment), women should be prepared for surgical resolution of pregnancy and clinicians should be able to perform an office-based procedure.

Expectant management
Women who choose the “watch and wait” approach should be advised that the process is unpredictable and occasionally requires urgent surgical intervention. Successful resolution of pregnancies that are expectantly managed depends on the type of miscarriage diagnosed at initial presentation. Luise and colleagues conducted a prospective study of 451 women with miscarriage who declined medical and surgical management. They found that the watch-and-wait approach was successful in 91% of women with an incomplete abortion, 76% of women with missed abortion, and 66% of women with anembryonic pregnancies.¹³ Success was defined by the absence of vaginal bleeding and an anterior-posterior endometrial stripe measuring less than 15 mm 4 weeks after initial diagnosis of miscarriage.

Like medical management for miscarriage, expectant management requires multiple office visits plus repeat ultrasounds or β-hCG measurement trends to confirm treatment success. Women who fail expectant management will require medical or surgical intervention to resolve the pregnancy. For those who are seeking pregnancy right away, the unpredictability and longer time to resolution of miscarriage may render expectant management anxiety provoking and unacceptable.

Etiology: Do true and perceived causes match?
Miscarriage during the first 13 weeks of gestation occurs in at least 10% of all clinically diagnosed pregnancies.¹⁰ A recent survey administered by Bardos and colleagues 
assessed perceived prevalence and causes of miscarriage in more than 1,000 US men and women.¹⁴ The majority of respondents believed miscarriage is uncommon, occurring in less than 5% of pregnancies. Respondents also believed stressful events, lifting heavy objects, and prior use of intrauterine or hormonal contraception are often to blame for pregnancy loss.

Despite more than 3 decades of data confirming that more than 60% of early losses are associated with chromosomal abnormalities and that an additional 18% may be associated with fetal anomalies, women often blame themselves.¹⁵ Bardos and colleagues found that 47% of women felt guilty about the experience of miscarriage.

Diagnosis: Updated ultrasonography criteria issued
When miscarriage is suspected based on symptoms of pain and bleeding in preg-
nancy, obtain a thorough history and conduct a limited physical examination. If an intrauterine pregnancy (IUP) was previously identified, a repeat ultrasound can confirm the presence or absence of the gestational sac. If an IUP has not been documented, then additional studies, including serial serum β-hCG examinations and ultrasonography, are essential to rule out ectopic pregnancy. Rh status should be determined and a 50-µg dose of Rh(D)-immune globulin administered to Rh(D)-unsensitized women within 72 hours of documented bleeding.

Ultrasonography is often used to diagnose miscarriage. Many gynecologists use ultrasound criteria based on studies conducted in the early 1990s that define nonviability by an empty gestational sac with mean gestational sac diameter greater than 16 mm or a crown-rump length (CRL) without evidence of fetal cardiac activity greater than 5 mm.¹⁰ In 2012, members of the Society of Radiologists in Ultrasound Multispecialty Panel on Early First Trimester Diagnosis of Miscarriage and Exclusion of a Viable Intrauterine Pregnancy developed more conservative criteria for the diagnosis of miscarriage.¹⁶

Doubilet and colleagues suggested new cutoffs, based on their reanalysis of 2 large prospective studies conducted in the United Kingdom.¹⁷ Calculations for these new cut-offs are based on mathematical adjustments for interobserver variability. Strict adherence to these more conservative criteria is sensible when a pregnancy is desired. For women who do not want to continue the pregnancy there is no medical justification for using this diagnostic process. Indeed, delays can lead to stress and poor outcomes including emergent surgical management for spontaneous and heavy bleeding.

Culture change is needed
Patients’ beliefs and scientific evidence about miscarriage are incongruous. By making simple changes in practice and providing straightforward patient education, ObGyns
can demystify the causes of miscarriage and improve its management. In particular, providing office-based MVA when requested can streamline treatment for many women. For too long, patients have blamed themselves for miscarriage and physicians have relied on D&C in the OR. Changes in culture surrounding miscarriage are 
long overdue.

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

Case Miscarriage in a 29-year-old woman
A woman (G0P0) presents to her gynecologist with amenorrhea for 3 months and a positive home urine pregnancy test. She is 29 years of age. She denies any bleeding or pain and intends to continue the pregnancy, though it was unplanned. Results of office ultrasonography to assess fetal viability reveal an intrauterine gestation with an 8-mm fetal pole but no heartbeat. The diagnosis is miscarriage.

This case illustrates a typical miscarriage diagnosis; most women with miscarriage are asymptomatic and without serious bleeding requiring emergency 
intervention. The management options include surgical, medical, and expectant. Women should be offered all 3 of these, and clinicians should explain the risks and benefits of each approach. But while each strategy can be safe, effective, and acceptable, many women, as well as their health care providers, will benefit from office-based uterine aspiration. In this article, we present the data available on office-based manual vacuum aspiration (MVA) as well as procedure pointers and urge you to consider MVA in your practice for your patients.

Surgical management
Surgical management of miscarriage offers several clear advantages over medical and expectant management. Perhaps the most important advantage to patients is that surgery offers rapid resolution of miscarriage with the shortest duration of bleeding.^1,2 When skilled providers perform electric vacuum aspiration (EVA) or MVA in outpatient or emergency department settings, successful uterine evacuation is completed in a single medical encounter 99% of the time.¹ By comparison, several follow-up visits and additional ultrasounds may be required during medical or expectant management. Uterine aspiration rarely requires an operating room (OR). Such a setting should be limited to cases in which the clinical picture reflects:

Office-based MVA
Office-based MVA is well tolerated when performed using a combination of verbal distraction and reassurance, oral nonsteroidal anti-inflammatory drugs (NSAIDs), and a paracervical block with or without intravenous sedation.

Evidence on managing pain at MVA. Multiple studies have assessed preprocedure and postprocedure pain using NSAIDs, oral anxiolytics, and local anesthesia at the time of EVA or MVA.^3,4 Renner and colleagues found that women who received a paracervical block prior to MVA or EVA reported moderate levels of pain, according to a 100-point visual analogue scale (VAS), at the time of cervical dilation (mean, 42) and uterine aspiration (mean, 63).⁴ In this same study, patients’ willingness to treat a future pregnancy with EVA or MVA using local anesthesia and their overall satisfaction with the procedure was high (mean, 90 on 100-point VAS).

In-office advantages over the OR. Women and clinicians can avoid the extensive scheduling delays associated with ORs, as well as the complications associated with medical and expectant management, if office-based EVA and MVA services are readily available. Compared with surgical management of miscarriage in an OR, office-based EVA and MVA are faster to complete. For example, Dalton and colleagues compared patients undergoing first-trimester procedures in an office setting with those undergoing a procedure in an OR. The mean procedure time for women treated in an office was 10 minutes, compared with 19 minutes for women treated in the OR. In addition, women 
treated in an office setting spent a mean total of 97 minutes at the office; women treated in an OR spent a mean total of 290 minutes at the hospital.⁵

Patients’ satisfaction with care provided in the OR was comparable to patients’ satisfaction with care provided in a medical office. In fact, the median total satisfaction score was high among women who had a procedure in either setting (office score, 19 of 20; OR score, 20 of 20).

Cost and equipment for in-office MVA
Office-based surgical management of miscarriage is more cost-effective than OR-based management. In 2006, Dalton and colleagues conducted a cost analysis and found that average charges for office-based MVA were less than half the cost of charges for a dilation and curettage (D&C) in the OR ($968 vs $1,965, respectively).⁵

More recently, these researchers found that usual care (expectant or OR management) was more costly than a model that also included medical and office-based surgical options. They found that the expanded care model—with use of the OR only when needed—cost $1,033.29 per case. This was compared with $1,247.58 per case when management options did not include medical and office-based surgical treatments.⁶

The cost of supplies needed to initiate MVA services within an established outpatient gynecologist’s office is modest. Equipment includes manual vacuum aspirators; disposable cannulae of various sizes; reusable plastic or metal dilators; supplies for disinfection, allowing reuse of MVA aspirators; and supplies for examination of products of conception (POC; FIGURE 1).

According to WomanCare Global, manufacturer of the IPAS MVA Plus, equipment should be sterilized after each use with soap and water, medical cleaning solution (such as Cidex, SPOROX II, etc.), or autoclaving.⁷ If 2 reusable aspirators are purchased along with dilators, disposable cannulae, and tools for tissue assessment, the price of supplies is estimated at US $500.⁸ WomanCare Global also offers prepackaged, single-use aspirator kits, which may be ideal for the emergency department setting.⁹

The procedure
To view a video on the MVA device and procedure, including step-by-step technique (FIGURE 2), local anesthesia administration, choosing cannula size, and cervical dilation, visit the Managing Early Pregnancy Loss Web site (http://www.earlypregnancylossresources.org) and access “Videos.” The video “Uterine aspiration for EPL” is available under password protection and broken into chapters for viewing ease.

The risk of endometritis after surgical management of miscarriage is low. Antibiotic prophylaxis prior to MVA or EVA should be considered. Experts recommend giving a single dose of doxycycline 200 mg orally at least 1 hour prior to uterine aspiration.^2,10

Use of EVA or MVA for outpatient management of miscarriage yields the opportunity to conduct immediate gross examination of the evacuated tissue and to verify the presence of complete POC. The process is simple: rinse the specimen through a sieve with water or saline, placed in a clear glass container under a small water bath and backlit on a light box. This allows clinicians to separate uterine decidua and pregnancy tissues. “Floating” tissue in this manner is especially useful in patients with pregnancy of unknown location, as immediate confirmation of a gestational sac rules out ectopic pregnancy.

Examine evacuated tissue for macroscopic evidence of pregnancy. Chorionic villi, which arise from syncytiotrophoblasts, can be seen with the naked eye. Immediate evaluation of POC is also useful for patients who desire diagnostic testing to ascertain a cause of their miscarriage because evacuated tissue stored in saline may be sent to a laboratory for cytogenetic analysis.

Medical management
Management of miscarriage with misoprostol is also safe and acceptable to women, though it has a lower success rate than surgical management.

Comparing efficacy: Medical vs surgical management. The Management of Early Pregnancy Failure Trial (MEPF) is the largest randomized controlled trial comparing medical management of miscarriage to surgical management. This multicenter study compared treatment with office-based EVA or MVA to vaginal misoprostol 800 µg. A repeat dose of vaginal misoprostol was offered 48 hours after the initial dose if a gestational sac was present on ultrasound.

Findings from the MEPF trial revealed a 71% complete uterine evacuation rate after 
1 dose of misoprostol and an 84% rate after 
2 doses.¹ The average (SD) reported pain score documented within 48 hours of treatment with misoprostol or MVA/EVA was moderate (5.7 cm [2.4] on 10-cm VAS). The rate of infection or hospitalization was less than 1% in both treatment groups.

These data should provide patients who are clinically stable and who wish to avoid an invasive procedure reassurance that using medication for the management of miscarriage is a reasonable option.

Misoprostol. Use of misoprostol is associated with a longer median duration of bleeding compared with suction aspiration. After misoprostol, bleeding usually begins after several hours and may continue for weeks.¹¹ Based on 2-week prospective bleeding diary entries from the MEPF trial, women who used misoprostol for management of miscarriage were more likely to have any bleeding during the 2 weeks after initiation of treatment, compared with women who had suction aspiration.¹²

Clinically significant changes in hemoglobin levels are more common in women treated with misoprostol than in those who choose EVA or MVA; however, these differences rarely require hospitalization or transfusion.¹ Women who are considering use of misoprostol should be aware of common adverse effects, including nausea, vomiting, diarrhea, and low-grade temperature.

Medical management of miscarriage requires multiple office visits with repeat ultrasounds or serum beta–human chorionic gonadotropin (β-hCG) levels to confirm treatment success. In cases of medication failure (persistent gestational sac with or without bleeding) or suspected retained POC (endometrial stripe greater than 
30 mm measured on ultrasound or persistent vaginal bleeding remote from treatment), women should be prepared for surgical resolution of pregnancy and clinicians should be able to perform an office-based procedure.

Expectant management
Women who choose the “watch and wait” approach should be advised that the process is unpredictable and occasionally requires urgent surgical intervention. Successful resolution of pregnancies that are expectantly managed depends on the type of miscarriage diagnosed at initial presentation. Luise and colleagues conducted a prospective study of 451 women with miscarriage who declined medical and surgical management. They found that the watch-and-wait approach was successful in 91% of women with an incomplete abortion, 76% of women with missed abortion, and 66% of women with anembryonic pregnancies.¹³ Success was defined by the absence of vaginal bleeding and an anterior-posterior endometrial stripe measuring less than 15 mm 4 weeks after initial diagnosis of miscarriage.

Like medical management for miscarriage, expectant management requires multiple office visits plus repeat ultrasounds or β-hCG measurement trends to confirm treatment success. Women who fail expectant management will require medical or surgical intervention to resolve the pregnancy. For those who are seeking pregnancy right away, the unpredictability and longer time to resolution of miscarriage may render expectant management anxiety provoking and unacceptable.

Etiology: Do true and perceived causes match?
Miscarriage during the first 13 weeks of gestation occurs in at least 10% of all clinically diagnosed pregnancies.¹⁰ A recent survey administered by Bardos and colleagues 
assessed perceived prevalence and causes of miscarriage in more than 1,000 US men and women.¹⁴ The majority of respondents believed miscarriage is uncommon, occurring in less than 5% of pregnancies. Respondents also believed stressful events, lifting heavy objects, and prior use of intrauterine or hormonal contraception are often to blame for pregnancy loss.

Despite more than 3 decades of data confirming that more than 60% of early losses are associated with chromosomal abnormalities and that an additional 18% may be associated with fetal anomalies, women often blame themselves.¹⁵ Bardos and colleagues found that 47% of women felt guilty about the experience of miscarriage.

Diagnosis: Updated ultrasonography criteria issued
When miscarriage is suspected based on symptoms of pain and bleeding in preg-
nancy, obtain a thorough history and conduct a limited physical examination. If an intrauterine pregnancy (IUP) was previously identified, a repeat ultrasound can confirm the presence or absence of the gestational sac. If an IUP has not been documented, then additional studies, including serial serum β-hCG examinations and ultrasonography, are essential to rule out ectopic pregnancy. Rh status should be determined and a 50-µg dose of Rh(D)-immune globulin administered to Rh(D)-unsensitized women within 72 hours of documented bleeding.

Ultrasonography is often used to diagnose miscarriage. Many gynecologists use ultrasound criteria based on studies conducted in the early 1990s that define nonviability by an empty gestational sac with mean gestational sac diameter greater than 16 mm or a crown-rump length (CRL) without evidence of fetal cardiac activity greater than 5 mm.¹⁰ In 2012, members of the Society of Radiologists in Ultrasound Multispecialty Panel on Early First Trimester Diagnosis of Miscarriage and Exclusion of a Viable Intrauterine Pregnancy developed more conservative criteria for the diagnosis of miscarriage.¹⁶

Doubilet and colleagues suggested new cutoffs, based on their reanalysis of 2 large prospective studies conducted in the United Kingdom.¹⁷ Calculations for these new cut-offs are based on mathematical adjustments for interobserver variability. Strict adherence to these more conservative criteria is sensible when a pregnancy is desired. For women who do not want to continue the pregnancy there is no medical justification for using this diagnostic process. Indeed, delays can lead to stress and poor outcomes including emergent surgical management for spontaneous and heavy bleeding.

Culture change is needed
Patients’ beliefs and scientific evidence about miscarriage are incongruous. By making simple changes in practice and providing straightforward patient education, ObGyns
can demystify the causes of miscarriage and improve its management. In particular, providing office-based MVA when requested can streamline treatment for many women. For too long, patients have blamed themselves for miscarriage and physicians have relied on D&C in the OR. Changes in culture surrounding miscarriage are 
long overdue.

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

Case Miscarriage in a 29-year-old woman
A woman (G0P0) presents to her gynecologist with amenorrhea for 3 months and a positive home urine pregnancy test. She is 29 years of age. She denies any bleeding or pain and intends to continue the pregnancy, though it was unplanned. Results of office ultrasonography to assess fetal viability reveal an intrauterine gestation with an 8-mm fetal pole but no heartbeat. The diagnosis is miscarriage.

This case illustrates a typical miscarriage diagnosis; most women with miscarriage are asymptomatic and without serious bleeding requiring emergency 
intervention. The management options include surgical, medical, and expectant. Women should be offered all 3 of these, and clinicians should explain the risks and benefits of each approach. But while each strategy can be safe, effective, and acceptable, many women, as well as their health care providers, will benefit from office-based uterine aspiration. In this article, we present the data available on office-based manual vacuum aspiration (MVA) as well as procedure pointers and urge you to consider MVA in your practice for your patients.

Surgical management
Surgical management of miscarriage offers several clear advantages over medical and expectant management. Perhaps the most important advantage to patients is that surgery offers rapid resolution of miscarriage with the shortest duration of bleeding.^1,2 When skilled providers perform electric vacuum aspiration (EVA) or MVA in outpatient or emergency department settings, successful uterine evacuation is completed in a single medical encounter 99% of the time.¹ By comparison, several follow-up visits and additional ultrasounds may be required during medical or expectant management. Uterine aspiration rarely requires an operating room (OR). Such a setting should be limited to cases in which the clinical picture reflects:

Office-based MVA
Office-based MVA is well tolerated when performed using a combination of verbal distraction and reassurance, oral nonsteroidal anti-inflammatory drugs (NSAIDs), and a paracervical block with or without intravenous sedation.

Evidence on managing pain at MVA. Multiple studies have assessed preprocedure and postprocedure pain using NSAIDs, oral anxiolytics, and local anesthesia at the time of EVA or MVA.^3,4 Renner and colleagues found that women who received a paracervical block prior to MVA or EVA reported moderate levels of pain, according to a 100-point visual analogue scale (VAS), at the time of cervical dilation (mean, 42) and uterine aspiration (mean, 63).⁴ In this same study, patients’ willingness to treat a future pregnancy with EVA or MVA using local anesthesia and their overall satisfaction with the procedure was high (mean, 90 on 100-point VAS).

In-office advantages over the OR. Women and clinicians can avoid the extensive scheduling delays associated with ORs, as well as the complications associated with medical and expectant management, if office-based EVA and MVA services are readily available. Compared with surgical management of miscarriage in an OR, office-based EVA and MVA are faster to complete. For example, Dalton and colleagues compared patients undergoing first-trimester procedures in an office setting with those undergoing a procedure in an OR. The mean procedure time for women treated in an office was 10 minutes, compared with 19 minutes for women treated in the OR. In addition, women 
treated in an office setting spent a mean total of 97 minutes at the office; women treated in an OR spent a mean total of 290 minutes at the hospital.⁵

Patients’ satisfaction with care provided in the OR was comparable to patients’ satisfaction with care provided in a medical office. In fact, the median total satisfaction score was high among women who had a procedure in either setting (office score, 19 of 20; OR score, 20 of 20).

Cost and equipment for in-office MVA
Office-based surgical management of miscarriage is more cost-effective than OR-based management. In 2006, Dalton and colleagues conducted a cost analysis and found that average charges for office-based MVA were less than half the cost of charges for a dilation and curettage (D&C) in the OR ($968 vs $1,965, respectively).⁵

More recently, these researchers found that usual care (expectant or OR management) was more costly than a model that also included medical and office-based surgical options. They found that the expanded care model—with use of the OR only when needed—cost $1,033.29 per case. This was compared with $1,247.58 per case when management options did not include medical and office-based surgical treatments.⁶

The cost of supplies needed to initiate MVA services within an established outpatient gynecologist’s office is modest. Equipment includes manual vacuum aspirators; disposable cannulae of various sizes; reusable plastic or metal dilators; supplies for disinfection, allowing reuse of MVA aspirators; and supplies for examination of products of conception (POC; FIGURE 1).

According to WomanCare Global, manufacturer of the IPAS MVA Plus, equipment should be sterilized after each use with soap and water, medical cleaning solution (such as Cidex, SPOROX II, etc.), or autoclaving.⁷ If 2 reusable aspirators are purchased along with dilators, disposable cannulae, and tools for tissue assessment, the price of supplies is estimated at US $500.⁸ WomanCare Global also offers prepackaged, single-use aspirator kits, which may be ideal for the emergency department setting.⁹

The procedure
To view a video on the MVA device and procedure, including step-by-step technique (FIGURE 2), local anesthesia administration, choosing cannula size, and cervical dilation, visit the Managing Early Pregnancy Loss Web site (http://www.earlypregnancylossresources.org) and access “Videos.” The video “Uterine aspiration for EPL” is available under password protection and broken into chapters for viewing ease.

The risk of endometritis after surgical management of miscarriage is low. Antibiotic prophylaxis prior to MVA or EVA should be considered. Experts recommend giving a single dose of doxycycline 200 mg orally at least 1 hour prior to uterine aspiration.^2,10

Use of EVA or MVA for outpatient management of miscarriage yields the opportunity to conduct immediate gross examination of the evacuated tissue and to verify the presence of complete POC. The process is simple: rinse the specimen through a sieve with water or saline, placed in a clear glass container under a small water bath and backlit on a light box. This allows clinicians to separate uterine decidua and pregnancy tissues. “Floating” tissue in this manner is especially useful in patients with pregnancy of unknown location, as immediate confirmation of a gestational sac rules out ectopic pregnancy.

Examine evacuated tissue for macroscopic evidence of pregnancy. Chorionic villi, which arise from syncytiotrophoblasts, can be seen with the naked eye. Immediate evaluation of POC is also useful for patients who desire diagnostic testing to ascertain a cause of their miscarriage because evacuated tissue stored in saline may be sent to a laboratory for cytogenetic analysis.

Medical management
Management of miscarriage with misoprostol is also safe and acceptable to women, though it has a lower success rate than surgical management.

Comparing efficacy: Medical vs surgical management. The Management of Early Pregnancy Failure Trial (MEPF) is the largest randomized controlled trial comparing medical management of miscarriage to surgical management. This multicenter study compared treatment with office-based EVA or MVA to vaginal misoprostol 800 µg. A repeat dose of vaginal misoprostol was offered 48 hours after the initial dose if a gestational sac was present on ultrasound.

Findings from the MEPF trial revealed a 71% complete uterine evacuation rate after 
1 dose of misoprostol and an 84% rate after 
2 doses.¹ The average (SD) reported pain score documented within 48 hours of treatment with misoprostol or MVA/EVA was moderate (5.7 cm [2.4] on 10-cm VAS). The rate of infection or hospitalization was less than 1% in both treatment groups.

These data should provide patients who are clinically stable and who wish to avoid an invasive procedure reassurance that using medication for the management of miscarriage is a reasonable option.

Misoprostol. Use of misoprostol is associated with a longer median duration of bleeding compared with suction aspiration. After misoprostol, bleeding usually begins after several hours and may continue for weeks.¹¹ Based on 2-week prospective bleeding diary entries from the MEPF trial, women who used misoprostol for management of miscarriage were more likely to have any bleeding during the 2 weeks after initiation of treatment, compared with women who had suction aspiration.¹²

Clinically significant changes in hemoglobin levels are more common in women treated with misoprostol than in those who choose EVA or MVA; however, these differences rarely require hospitalization or transfusion.¹ Women who are considering use of misoprostol should be aware of common adverse effects, including nausea, vomiting, diarrhea, and low-grade temperature.

Medical management of miscarriage requires multiple office visits with repeat ultrasounds or serum beta–human chorionic gonadotropin (β-hCG) levels to confirm treatment success. In cases of medication failure (persistent gestational sac with or without bleeding) or suspected retained POC (endometrial stripe greater than 
30 mm measured on ultrasound or persistent vaginal bleeding remote from treatment), women should be prepared for surgical resolution of pregnancy and clinicians should be able to perform an office-based procedure.

Expectant management
Women who choose the “watch and wait” approach should be advised that the process is unpredictable and occasionally requires urgent surgical intervention. Successful resolution of pregnancies that are expectantly managed depends on the type of miscarriage diagnosed at initial presentation. Luise and colleagues conducted a prospective study of 451 women with miscarriage who declined medical and surgical management. They found that the watch-and-wait approach was successful in 91% of women with an incomplete abortion, 76% of women with missed abortion, and 66% of women with anembryonic pregnancies.¹³ Success was defined by the absence of vaginal bleeding and an anterior-posterior endometrial stripe measuring less than 15 mm 4 weeks after initial diagnosis of miscarriage.

Like medical management for miscarriage, expectant management requires multiple office visits plus repeat ultrasounds or β-hCG measurement trends to confirm treatment success. Women who fail expectant management will require medical or surgical intervention to resolve the pregnancy. For those who are seeking pregnancy right away, the unpredictability and longer time to resolution of miscarriage may render expectant management anxiety provoking and unacceptable.

Etiology: Do true and perceived causes match?
Miscarriage during the first 13 weeks of gestation occurs in at least 10% of all clinically diagnosed pregnancies.¹⁰ A recent survey administered by Bardos and colleagues 
assessed perceived prevalence and causes of miscarriage in more than 1,000 US men and women.¹⁴ The majority of respondents believed miscarriage is uncommon, occurring in less than 5% of pregnancies. Respondents also believed stressful events, lifting heavy objects, and prior use of intrauterine or hormonal contraception are often to blame for pregnancy loss.

Despite more than 3 decades of data confirming that more than 60% of early losses are associated with chromosomal abnormalities and that an additional 18% may be associated with fetal anomalies, women often blame themselves.¹⁵ Bardos and colleagues found that 47% of women felt guilty about the experience of miscarriage.

Diagnosis: Updated ultrasonography criteria issued
When miscarriage is suspected based on symptoms of pain and bleeding in preg-
nancy, obtain a thorough history and conduct a limited physical examination. If an intrauterine pregnancy (IUP) was previously identified, a repeat ultrasound can confirm the presence or absence of the gestational sac. If an IUP has not been documented, then additional studies, including serial serum β-hCG examinations and ultrasonography, are essential to rule out ectopic pregnancy. Rh status should be determined and a 50-µg dose of Rh(D)-immune globulin administered to Rh(D)-unsensitized women within 72 hours of documented bleeding.

Ultrasonography is often used to diagnose miscarriage. Many gynecologists use ultrasound criteria based on studies conducted in the early 1990s that define nonviability by an empty gestational sac with mean gestational sac diameter greater than 16 mm or a crown-rump length (CRL) without evidence of fetal cardiac activity greater than 5 mm.¹⁰ In 2012, members of the Society of Radiologists in Ultrasound Multispecialty Panel on Early First Trimester Diagnosis of Miscarriage and Exclusion of a Viable Intrauterine Pregnancy developed more conservative criteria for the diagnosis of miscarriage.¹⁶

Doubilet and colleagues suggested new cutoffs, based on their reanalysis of 2 large prospective studies conducted in the United Kingdom.¹⁷ Calculations for these new cut-offs are based on mathematical adjustments for interobserver variability. Strict adherence to these more conservative criteria is sensible when a pregnancy is desired. For women who do not want to continue the pregnancy there is no medical justification for using this diagnostic process. Indeed, delays can lead to stress and poor outcomes including emergent surgical management for spontaneous and heavy bleeding.

Culture change is needed
Patients’ beliefs and scientific evidence about miscarriage are incongruous. By making simple changes in practice and providing straightforward patient education, ObGyns
can demystify the causes of miscarriage and improve its management. In particular, providing office-based MVA when requested can streamline treatment for many women. For too long, patients have blamed themselves for miscarriage and physicians have relied on D&C in the OR. Changes in culture surrounding miscarriage are 
long overdue.

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

After a busy day in the primary care clinic, having finished the day’s dictations and called a patient to discuss the results of his lipid panel, Dr. B reviews tomorrow’s schedule, and notices 2 patients with a primary diagnosis of chronic obstructive pulmonary disease (COPD). Dr. B recalls a recent publication on changes in the classification of COPD by the Global Initiative for Chronic Obstructive Lung Disease (GOLD).¹ She remembers the main message being the degree of airway obstruction as measured by the forced expiratory volume in the first second (FEV₁) is now considered insufficient to classify COPD severity and to make a therapeutic decision. This paradigm shift contradicts the familiar concept that FEV₁ is the cornerstone piece of information in COPD, resulting in some degree of uncertainty about how to apply this in the practice. Dr. B. considers a multitude of practical questions, including: Is there a good reason to change the classification of COPD? How easy is it to use?

Will it make any therapeutic differences to my patients? In this article, the authors attempt to answer these and other questions prompted by the recent changes in the GOLD classification, with emphasis on its clinical use.

A Heterogeneous Condition

Spirometry is central to the diagnosis of obstructive lung diseases, including COPD and asthma. The diagnosis of COPD requires demonstration of an obstructive ventilatory defect in the spirometry, usually defined as a ratio of FEV1 to forced vital capacity (FVC) below 70% (FEV1/FVC < 0.7). FEV1 is still important, not only to confirm the diagnosis of airflow obstruction, but because it predicts mortality when severely reduced. However, during the last decade severity of airflow limitation has been challenged as a descriptor of both symptom burden and consequences of COPD by data from large studies.² For example, it has been demonstrated that 2 patients with the same degree of obstruction, measured by the FEV1 percentage predicted, can provide the physician with very different experiences about the impact of their disease in daily life.³ These differences extend to the severity of their dyspnea; their exercise capacity, as seen in the sixminute walking distance test (6MWD); or their perceived quality of life (QOL), measured by the score on the Saint George’s Respiratory Questionnaire (SGRQ). These measures of disease impact show an extremely low correlation with FEV1: a correlation of 0.36 with the severity of dyspnea, 0.34 with 6MWD, and 0.38 with the SGRQ total score.² These newer studies imply that while spirometry is important, it captures only a small portion of the symptomatic and functional impact of COPD.

Increasing interest in understanding the differences between COPD subjects has been the main motivation in identifying distinct COPD phenotypes, subgroups of patients with similar disease experience, probable similar underlying pathogenic mechanisms, similar outcomes, and perhaps specific treatment alternatives.^4,5 The severity of airflow limitation, as measured by FEV1 percent predicted, is not always related with some of the emerging COPD phenotypes (eg, chronic bronchitis predominant phenotype, frequent exacerbation phenotype).^6-8 Chronic bronchitis can be present across the whole spectrum of spirometry severity, and is always associated with poorer QOL and worse clinical outcomes. Similarly, there are patients with frequent exacerbation phenotype (defined as ≥ 2 exacerbations/year) at every level of airflow obstruction, and the phenotype tends to be stable, meaning that previous frequent exacerbations are a good predictor of future exacerbations.⁸

With all this information, participants in the development of the GOLD guidelines determined that although FEV1 is still a good descriptor of COPD severity and potential for poor outcomes (exacerbation frequency, mortality), a more comprehensive description of COPD needed the addition of data on the impact of symptoms (particularly dyspnea), and the future risk of poor COPD related events (exacerbations, death, disease progression).⁵ Hence, in response to Dr. B.’s question, it seems that a new approach to the way that we classify COPD was overdue, making it important to gather additional patient information, beyond FEV₁.

GOLD Category Classification

An important difference from previous classifications is that the new GOLD categories use lettered groups, from A to D, not just grades of severity; however, the severity of the ventilatory defect measured by FEV1 is still graded from 1 to 4 and is still part of the classification.9

Placing a patient in the new groups is based on 2 questions: (1) How severe are the symptoms, particularly dyspnea; and (2) Is the patient at high or low risk of poor COPD-related outcomes? The first question (symptoms severity) can be systematically approached using 1 of 2 different instruments to grade COPD symptoms: the modified Medical Research Council dyspnea score (mMRC) or the COPD Assessment Test (CAT), a more recently developed instrument to quantify COPD impact.10,11

Use of CAT score, a more comprehensive descriptor of COPD impact, is the preferred method by guideline developers. If the practitioner is more familiar with the mMRC and wishes to use it instead, the result can be simplified as low (0-1 points) or high symptoms burden (≥ 2 points). The mMRC is based on the answer to the level of effort triggering dyspnea: a score of 1 means that the patient “get[s] shorter of breath when hurrying on a level surface or walking up a slight hill”; a score of 2 means that the patient “walk[s] slower than people of the same age while walking on a level surface because of breathlessness, or I have to stop for breath when walking on my own pace on the level.” Hence, the first step to classify a patient can be as simple as asking about dyspnea, surely part of the history taking process.

The second question (risk of poor COPD-related outcomes) can be answered by using the grade of obstruction by FEV₁ or asking about the frequency of exacerbations in the previous year. If FEV1 is used, those with FEV₁ percentage predicted ≥ 50% are considered as “low risk”; if the airflow obstruction is more severe (previously grades 3-4), the patient is at “high risk” of future events. If the exacerbation frequency is used, ≤ 1 outpatient-treated exacerbation in the previous year qualify as “low,” and ≥ 2 as “high risk.” There is an additional alternative way to identify high risk: all patients with any (≥ 1 per year) exacerbation requiring hospital admission are considered at high risk.

The next step is combining both symptoms and risk to create 4 mutually exclusive groups, which will be relevant to select the appropriate treatment (Table 1). The groups can also be represented graphically using a 2x2 figure, with the horizontal axis being symptoms severity, and the vertical (risk) either FEV1 or exacerbation history (Figure 1). If there is a discrepancy between the risk judged by lung function and history of exacerbations, it is recommended to use the answer corresponding to the worse category.¹²

GOLD Guideline-Based Treatment

The new classification should also help to identify the patient’s main needs: controlling symptoms, reducing future risks, or both. Based on the results of available randomized clinical trials, GOLD guideline developers suggest grouptailored strategies of management (Table 2, Figure 2).

Group A: Low Risk and Low Symptoms

The goal is to treat only as needed, using shortacting medications. No preference was given to the type of short-acting medication and the practitioner could select between short-acting beta agonists (SABAs) or short-acting anticholinergic (also known as short-acting antimuscarinic [SAMA]) medication as first-line therapy. Second-line therapy includes either the combination of both families of short-acting medications in 1 inhaler, or the use of 1 long-acting inhaler. As a rule of thumb, no patient in this group should be on more than 1 inhaler, and the combination of short and long-acting medications is not part of the recommendations. Patients in group A, and indeed everyone with COPD, benefit from respiratory immunizations and tobacco cessation.

Group B: Low Risk, High Symptoms

Again, the goal of treatment is symptom control. Based on the available evidence, this can be achieved using long-acting bronchodilators, without the need of inhaled corticosteroids (ICS). The first line of treatment should be just 1 bronchodilator, either a long-acting antimuscarinic (LAMA) or long-actingbeta agonist (LABA). These could be used together as second-line treatment (LAMA plus LABA), still without indication for ICS. It is important to remember that dyspnea, or other symptoms, could also be a manifestation of comorbid conditions, such as cardiovascular disease, obesity, deconditioning, and musculoskeletal diseases.¹³ When spirometry is not used to confirm the diagnosis of COPD, patients may receive incremental types of inhalers instead of being evaluated for other causes of dyspnea, which might have led to more appropriate specific therapy.¹⁴ As a result, judicious evaluation of the patient’s symptomsis recommended. The guidelines also recommend programs that increase physical activity for this group of patients, as well to those in groups C and D, as this can improve symptoms and decrease risk of exacerbations.¹⁵

Group C: High Risk, Low Symptoms

The combination of ICS/LABA is the first-line therapy for this group, based on data showing the superiority of the ICS/LABA combination over monotherapy to reduce exacerbations and symptoms, as well as to improve QOL.^16,17 Monotherapy LABA is also a first-line GOLD recommendation. Selecting between ICS/LABA vs LABA should be individualized based on the reason that the patient was judged as high risk. In the authors’ practice, if
the risk is based only in spirometry values, using LABA as monotherapy is a good choice, while if the definition of high risk was based on the frequency of exacerbations, ICS/LABA is the first choice. The GOLD guidelines list the combination of LABA/LAMA as second-line therapy.

Group D: High Risk and High Symptoms

First-line therapy for this group is essentially the same that for group C, with similar considerations. The combination of LABA/LAMA is also recommended as second-line therapy, as well as the use of ICS/LABA and LAMA (all 3 major classes of controller medications together). It is worth noting that phosphodiesterase-4 inhibitors (PDE4-inh, roflumilast being the best known) can be considered as a third-line of therapy (in group C) or as part of secondline combinations (in group D).

Benefits and Limitations of GOLD

There is no doubt that the new classification system and treatment guidelines are a significant step forward, intended to foster the development of more personalized decisions for COPD patients. The guidelines are the first attempt to incorporate the concepts of phenotypes (frequent exacerbation phenotype), disease heterogeneity (the variation in outcomes for the same degree of airflow obstruction), and the differences between the burden of symptoms and the risk of outcomes. The guidelines incorporate the need to weigh the benefits and risks of medications at the individual level (eg, ICS without an accompanying long-acting agent are not recommended in any group, and ICS use is reserved for those with high risk, especially if the designation is based on exacerbation frequency). The guidelines also stress the importance of examining comorbidities, emphysizing that their management should in no way be altered just because the patient also has COPD. Relative to the previous staging based only on FEV₁ values, this new classification system has been shown to have appropriate predictive ability and association with the risk of exacerbations, and better correlation with measures of quality of life and costs of care.^18,19 The guidelines, initially released in 2011 and slightly updated recently, are in continuous development and have been subject to intense evaluation.

Some limitations have been found (eg, the classification is still not the best predictor of mortality, but has the same ability to predict hospital admission as the previous spirometry-based system).^18,20,21 Hence, it should be no surprise that modifications will likely be released in the near future.

The treatment recommendations associated with the current classification are based on the best evidence available and expert opinion, as no published clinical trials have compared the group-based therapy system to standard therapies. Evaluations of their effectiveness in real-life practice are still to be released. Previous, less complex guidelines, based on spirometry stages, were followed < 60% of the time in actual practice, thus it will be surprising to find high adherence to the current recommendations, but evaluations are still in progress.²²

Conclusion

The best way for primary care providers to incorporate the GOLD guidelines into daily practice is to remember that COPD is very heterogeneous. Although spirometry is important, it is also essential to inquire about exacerbation frequency and symptoms severity. It is encouraging that for each of the relevant questions needed to classify the patient, there is a clear, easy to remember cut point. First, look at symptoms (low or high burden, based on the presence of dyspnea), then to judge risk look at FEV₁ percentage predicted (using 50% as a cutpoint) and at exacerbation frequency (using 2 per year as the cut point). With those simple questions, build the groups, based on the combination of answers, and select the appropriate therapy. The general assumptions are that short-acting medications are appropriate for infrequent symptoms, long-acting medications are used to control symptoms and prevent exacerbations in more severe disease, and that ICS (always in combination with LABA) are reserved for those in the high-risk groups, especially if high risk is defined by frequent exacerbations. This summary should be supplemented with the judicious use of the tables and figures provided in this review, and available with detailed description and discussion in the original sources.¹

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner; Frontline Medical Communications Inc.; the Department of Defense, or its Components; and the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

After a busy day in the primary care clinic, having finished the day’s dictations and called a patient to discuss the results of his lipid panel, Dr. B reviews tomorrow’s schedule, and notices 2 patients with a primary diagnosis of chronic obstructive pulmonary disease (COPD). Dr. B recalls a recent publication on changes in the classification of COPD by the Global Initiative for Chronic Obstructive Lung Disease (GOLD).¹ She remembers the main message being the degree of airway obstruction as measured by the forced expiratory volume in the first second (FEV₁) is now considered insufficient to classify COPD severity and to make a therapeutic decision. This paradigm shift contradicts the familiar concept that FEV₁ is the cornerstone piece of information in COPD, resulting in some degree of uncertainty about how to apply this in the practice. Dr. B. considers a multitude of practical questions, including: Is there a good reason to change the classification of COPD? How easy is it to use?

Will it make any therapeutic differences to my patients? In this article, the authors attempt to answer these and other questions prompted by the recent changes in the GOLD classification, with emphasis on its clinical use.

A Heterogeneous Condition

Spirometry is central to the diagnosis of obstructive lung diseases, including COPD and asthma. The diagnosis of COPD requires demonstration of an obstructive ventilatory defect in the spirometry, usually defined as a ratio of FEV1 to forced vital capacity (FVC) below 70% (FEV1/FVC < 0.7). FEV1 is still important, not only to confirm the diagnosis of airflow obstruction, but because it predicts mortality when severely reduced. However, during the last decade severity of airflow limitation has been challenged as a descriptor of both symptom burden and consequences of COPD by data from large studies.² For example, it has been demonstrated that 2 patients with the same degree of obstruction, measured by the FEV1 percentage predicted, can provide the physician with very different experiences about the impact of their disease in daily life.³ These differences extend to the severity of their dyspnea; their exercise capacity, as seen in the sixminute walking distance test (6MWD); or their perceived quality of life (QOL), measured by the score on the Saint George’s Respiratory Questionnaire (SGRQ). These measures of disease impact show an extremely low correlation with FEV1: a correlation of 0.36 with the severity of dyspnea, 0.34 with 6MWD, and 0.38 with the SGRQ total score.² These newer studies imply that while spirometry is important, it captures only a small portion of the symptomatic and functional impact of COPD.

Increasing interest in understanding the differences between COPD subjects has been the main motivation in identifying distinct COPD phenotypes, subgroups of patients with similar disease experience, probable similar underlying pathogenic mechanisms, similar outcomes, and perhaps specific treatment alternatives.^4,5 The severity of airflow limitation, as measured by FEV1 percent predicted, is not always related with some of the emerging COPD phenotypes (eg, chronic bronchitis predominant phenotype, frequent exacerbation phenotype).^6-8 Chronic bronchitis can be present across the whole spectrum of spirometry severity, and is always associated with poorer QOL and worse clinical outcomes. Similarly, there are patients with frequent exacerbation phenotype (defined as ≥ 2 exacerbations/year) at every level of airflow obstruction, and the phenotype tends to be stable, meaning that previous frequent exacerbations are a good predictor of future exacerbations.⁸

With all this information, participants in the development of the GOLD guidelines determined that although FEV1 is still a good descriptor of COPD severity and potential for poor outcomes (exacerbation frequency, mortality), a more comprehensive description of COPD needed the addition of data on the impact of symptoms (particularly dyspnea), and the future risk of poor COPD related events (exacerbations, death, disease progression).⁵ Hence, in response to Dr. B.’s question, it seems that a new approach to the way that we classify COPD was overdue, making it important to gather additional patient information, beyond FEV₁.

GOLD Category Classification

An important difference from previous classifications is that the new GOLD categories use lettered groups, from A to D, not just grades of severity; however, the severity of the ventilatory defect measured by FEV1 is still graded from 1 to 4 and is still part of the classification.9

Placing a patient in the new groups is based on 2 questions: (1) How severe are the symptoms, particularly dyspnea; and (2) Is the patient at high or low risk of poor COPD-related outcomes? The first question (symptoms severity) can be systematically approached using 1 of 2 different instruments to grade COPD symptoms: the modified Medical Research Council dyspnea score (mMRC) or the COPD Assessment Test (CAT), a more recently developed instrument to quantify COPD impact.10,11

Use of CAT score, a more comprehensive descriptor of COPD impact, is the preferred method by guideline developers. If the practitioner is more familiar with the mMRC and wishes to use it instead, the result can be simplified as low (0-1 points) or high symptoms burden (≥ 2 points). The mMRC is based on the answer to the level of effort triggering dyspnea: a score of 1 means that the patient “get[s] shorter of breath when hurrying on a level surface or walking up a slight hill”; a score of 2 means that the patient “walk[s] slower than people of the same age while walking on a level surface because of breathlessness, or I have to stop for breath when walking on my own pace on the level.” Hence, the first step to classify a patient can be as simple as asking about dyspnea, surely part of the history taking process.

The second question (risk of poor COPD-related outcomes) can be answered by using the grade of obstruction by FEV₁ or asking about the frequency of exacerbations in the previous year. If FEV1 is used, those with FEV₁ percentage predicted ≥ 50% are considered as “low risk”; if the airflow obstruction is more severe (previously grades 3-4), the patient is at “high risk” of future events. If the exacerbation frequency is used, ≤ 1 outpatient-treated exacerbation in the previous year qualify as “low,” and ≥ 2 as “high risk.” There is an additional alternative way to identify high risk: all patients with any (≥ 1 per year) exacerbation requiring hospital admission are considered at high risk.

The next step is combining both symptoms and risk to create 4 mutually exclusive groups, which will be relevant to select the appropriate treatment (Table 1). The groups can also be represented graphically using a 2x2 figure, with the horizontal axis being symptoms severity, and the vertical (risk) either FEV1 or exacerbation history (Figure 1). If there is a discrepancy between the risk judged by lung function and history of exacerbations, it is recommended to use the answer corresponding to the worse category.¹²

GOLD Guideline-Based Treatment

The new classification should also help to identify the patient’s main needs: controlling symptoms, reducing future risks, or both. Based on the results of available randomized clinical trials, GOLD guideline developers suggest grouptailored strategies of management (Table 2, Figure 2).

Group A: Low Risk and Low Symptoms

The goal is to treat only as needed, using shortacting medications. No preference was given to the type of short-acting medication and the practitioner could select between short-acting beta agonists (SABAs) or short-acting anticholinergic (also known as short-acting antimuscarinic [SAMA]) medication as first-line therapy. Second-line therapy includes either the combination of both families of short-acting medications in 1 inhaler, or the use of 1 long-acting inhaler. As a rule of thumb, no patient in this group should be on more than 1 inhaler, and the combination of short and long-acting medications is not part of the recommendations. Patients in group A, and indeed everyone with COPD, benefit from respiratory immunizations and tobacco cessation.

Group B: Low Risk, High Symptoms

Again, the goal of treatment is symptom control. Based on the available evidence, this can be achieved using long-acting bronchodilators, without the need of inhaled corticosteroids (ICS). The first line of treatment should be just 1 bronchodilator, either a long-acting antimuscarinic (LAMA) or long-actingbeta agonist (LABA). These could be used together as second-line treatment (LAMA plus LABA), still without indication for ICS. It is important to remember that dyspnea, or other symptoms, could also be a manifestation of comorbid conditions, such as cardiovascular disease, obesity, deconditioning, and musculoskeletal diseases.¹³ When spirometry is not used to confirm the diagnosis of COPD, patients may receive incremental types of inhalers instead of being evaluated for other causes of dyspnea, which might have led to more appropriate specific therapy.¹⁴ As a result, judicious evaluation of the patient’s symptomsis recommended. The guidelines also recommend programs that increase physical activity for this group of patients, as well to those in groups C and D, as this can improve symptoms and decrease risk of exacerbations.¹⁵

Group C: High Risk, Low Symptoms

The combination of ICS/LABA is the first-line therapy for this group, based on data showing the superiority of the ICS/LABA combination over monotherapy to reduce exacerbations and symptoms, as well as to improve QOL.^16,17 Monotherapy LABA is also a first-line GOLD recommendation. Selecting between ICS/LABA vs LABA should be individualized based on the reason that the patient was judged as high risk. In the authors’ practice, if
the risk is based only in spirometry values, using LABA as monotherapy is a good choice, while if the definition of high risk was based on the frequency of exacerbations, ICS/LABA is the first choice. The GOLD guidelines list the combination of LABA/LAMA as second-line therapy.

Group D: High Risk and High Symptoms

First-line therapy for this group is essentially the same that for group C, with similar considerations. The combination of LABA/LAMA is also recommended as second-line therapy, as well as the use of ICS/LABA and LAMA (all 3 major classes of controller medications together). It is worth noting that phosphodiesterase-4 inhibitors (PDE4-inh, roflumilast being the best known) can be considered as a third-line of therapy (in group C) or as part of secondline combinations (in group D).

Benefits and Limitations of GOLD

There is no doubt that the new classification system and treatment guidelines are a significant step forward, intended to foster the development of more personalized decisions for COPD patients. The guidelines are the first attempt to incorporate the concepts of phenotypes (frequent exacerbation phenotype), disease heterogeneity (the variation in outcomes for the same degree of airflow obstruction), and the differences between the burden of symptoms and the risk of outcomes. The guidelines incorporate the need to weigh the benefits and risks of medications at the individual level (eg, ICS without an accompanying long-acting agent are not recommended in any group, and ICS use is reserved for those with high risk, especially if the designation is based on exacerbation frequency). The guidelines also stress the importance of examining comorbidities, emphysizing that their management should in no way be altered just because the patient also has COPD. Relative to the previous staging based only on FEV₁ values, this new classification system has been shown to have appropriate predictive ability and association with the risk of exacerbations, and better correlation with measures of quality of life and costs of care.^18,19 The guidelines, initially released in 2011 and slightly updated recently, are in continuous development and have been subject to intense evaluation.

Some limitations have been found (eg, the classification is still not the best predictor of mortality, but has the same ability to predict hospital admission as the previous spirometry-based system).^18,20,21 Hence, it should be no surprise that modifications will likely be released in the near future.

The treatment recommendations associated with the current classification are based on the best evidence available and expert opinion, as no published clinical trials have compared the group-based therapy system to standard therapies. Evaluations of their effectiveness in real-life practice are still to be released. Previous, less complex guidelines, based on spirometry stages, were followed < 60% of the time in actual practice, thus it will be surprising to find high adherence to the current recommendations, but evaluations are still in progress.²²

Conclusion

The best way for primary care providers to incorporate the GOLD guidelines into daily practice is to remember that COPD is very heterogeneous. Although spirometry is important, it is also essential to inquire about exacerbation frequency and symptoms severity. It is encouraging that for each of the relevant questions needed to classify the patient, there is a clear, easy to remember cut point. First, look at symptoms (low or high burden, based on the presence of dyspnea), then to judge risk look at FEV₁ percentage predicted (using 50% as a cutpoint) and at exacerbation frequency (using 2 per year as the cut point). With those simple questions, build the groups, based on the combination of answers, and select the appropriate therapy. The general assumptions are that short-acting medications are appropriate for infrequent symptoms, long-acting medications are used to control symptoms and prevent exacerbations in more severe disease, and that ICS (always in combination with LABA) are reserved for those in the high-risk groups, especially if high risk is defined by frequent exacerbations. This summary should be supplemented with the judicious use of the tables and figures provided in this review, and available with detailed description and discussion in the original sources.¹

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner; Frontline Medical Communications Inc.; the Department of Defense, or its Components; and the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

After a busy day in the primary care clinic, having finished the day’s dictations and called a patient to discuss the results of his lipid panel, Dr. B reviews tomorrow’s schedule, and notices 2 patients with a primary diagnosis of chronic obstructive pulmonary disease (COPD). Dr. B recalls a recent publication on changes in the classification of COPD by the Global Initiative for Chronic Obstructive Lung Disease (GOLD).¹ She remembers the main message being the degree of airway obstruction as measured by the forced expiratory volume in the first second (FEV₁) is now considered insufficient to classify COPD severity and to make a therapeutic decision. This paradigm shift contradicts the familiar concept that FEV₁ is the cornerstone piece of information in COPD, resulting in some degree of uncertainty about how to apply this in the practice. Dr. B. considers a multitude of practical questions, including: Is there a good reason to change the classification of COPD? How easy is it to use?

Will it make any therapeutic differences to my patients? In this article, the authors attempt to answer these and other questions prompted by the recent changes in the GOLD classification, with emphasis on its clinical use.

A Heterogeneous Condition

Spirometry is central to the diagnosis of obstructive lung diseases, including COPD and asthma. The diagnosis of COPD requires demonstration of an obstructive ventilatory defect in the spirometry, usually defined as a ratio of FEV1 to forced vital capacity (FVC) below 70% (FEV1/FVC < 0.7). FEV1 is still important, not only to confirm the diagnosis of airflow obstruction, but because it predicts mortality when severely reduced. However, during the last decade severity of airflow limitation has been challenged as a descriptor of both symptom burden and consequences of COPD by data from large studies.² For example, it has been demonstrated that 2 patients with the same degree of obstruction, measured by the FEV1 percentage predicted, can provide the physician with very different experiences about the impact of their disease in daily life.³ These differences extend to the severity of their dyspnea; their exercise capacity, as seen in the sixminute walking distance test (6MWD); or their perceived quality of life (QOL), measured by the score on the Saint George’s Respiratory Questionnaire (SGRQ). These measures of disease impact show an extremely low correlation with FEV1: a correlation of 0.36 with the severity of dyspnea, 0.34 with 6MWD, and 0.38 with the SGRQ total score.² These newer studies imply that while spirometry is important, it captures only a small portion of the symptomatic and functional impact of COPD.

Increasing interest in understanding the differences between COPD subjects has been the main motivation in identifying distinct COPD phenotypes, subgroups of patients with similar disease experience, probable similar underlying pathogenic mechanisms, similar outcomes, and perhaps specific treatment alternatives.^4,5 The severity of airflow limitation, as measured by FEV1 percent predicted, is not always related with some of the emerging COPD phenotypes (eg, chronic bronchitis predominant phenotype, frequent exacerbation phenotype).^6-8 Chronic bronchitis can be present across the whole spectrum of spirometry severity, and is always associated with poorer QOL and worse clinical outcomes. Similarly, there are patients with frequent exacerbation phenotype (defined as ≥ 2 exacerbations/year) at every level of airflow obstruction, and the phenotype tends to be stable, meaning that previous frequent exacerbations are a good predictor of future exacerbations.⁸

With all this information, participants in the development of the GOLD guidelines determined that although FEV1 is still a good descriptor of COPD severity and potential for poor outcomes (exacerbation frequency, mortality), a more comprehensive description of COPD needed the addition of data on the impact of symptoms (particularly dyspnea), and the future risk of poor COPD related events (exacerbations, death, disease progression).⁵ Hence, in response to Dr. B.’s question, it seems that a new approach to the way that we classify COPD was overdue, making it important to gather additional patient information, beyond FEV₁.

GOLD Category Classification

An important difference from previous classifications is that the new GOLD categories use lettered groups, from A to D, not just grades of severity; however, the severity of the ventilatory defect measured by FEV1 is still graded from 1 to 4 and is still part of the classification.9

Placing a patient in the new groups is based on 2 questions: (1) How severe are the symptoms, particularly dyspnea; and (2) Is the patient at high or low risk of poor COPD-related outcomes? The first question (symptoms severity) can be systematically approached using 1 of 2 different instruments to grade COPD symptoms: the modified Medical Research Council dyspnea score (mMRC) or the COPD Assessment Test (CAT), a more recently developed instrument to quantify COPD impact.10,11

Use of CAT score, a more comprehensive descriptor of COPD impact, is the preferred method by guideline developers. If the practitioner is more familiar with the mMRC and wishes to use it instead, the result can be simplified as low (0-1 points) or high symptoms burden (≥ 2 points). The mMRC is based on the answer to the level of effort triggering dyspnea: a score of 1 means that the patient “get[s] shorter of breath when hurrying on a level surface or walking up a slight hill”; a score of 2 means that the patient “walk[s] slower than people of the same age while walking on a level surface because of breathlessness, or I have to stop for breath when walking on my own pace on the level.” Hence, the first step to classify a patient can be as simple as asking about dyspnea, surely part of the history taking process.

The second question (risk of poor COPD-related outcomes) can be answered by using the grade of obstruction by FEV₁ or asking about the frequency of exacerbations in the previous year. If FEV1 is used, those with FEV₁ percentage predicted ≥ 50% are considered as “low risk”; if the airflow obstruction is more severe (previously grades 3-4), the patient is at “high risk” of future events. If the exacerbation frequency is used, ≤ 1 outpatient-treated exacerbation in the previous year qualify as “low,” and ≥ 2 as “high risk.” There is an additional alternative way to identify high risk: all patients with any (≥ 1 per year) exacerbation requiring hospital admission are considered at high risk.

The next step is combining both symptoms and risk to create 4 mutually exclusive groups, which will be relevant to select the appropriate treatment (Table 1). The groups can also be represented graphically using a 2x2 figure, with the horizontal axis being symptoms severity, and the vertical (risk) either FEV1 or exacerbation history (Figure 1). If there is a discrepancy between the risk judged by lung function and history of exacerbations, it is recommended to use the answer corresponding to the worse category.¹²

GOLD Guideline-Based Treatment

The new classification should also help to identify the patient’s main needs: controlling symptoms, reducing future risks, or both. Based on the results of available randomized clinical trials, GOLD guideline developers suggest grouptailored strategies of management (Table 2, Figure 2).

Group A: Low Risk and Low Symptoms

The goal is to treat only as needed, using shortacting medications. No preference was given to the type of short-acting medication and the practitioner could select between short-acting beta agonists (SABAs) or short-acting anticholinergic (also known as short-acting antimuscarinic [SAMA]) medication as first-line therapy. Second-line therapy includes either the combination of both families of short-acting medications in 1 inhaler, or the use of 1 long-acting inhaler. As a rule of thumb, no patient in this group should be on more than 1 inhaler, and the combination of short and long-acting medications is not part of the recommendations. Patients in group A, and indeed everyone with COPD, benefit from respiratory immunizations and tobacco cessation.

Group B: Low Risk, High Symptoms

Again, the goal of treatment is symptom control. Based on the available evidence, this can be achieved using long-acting bronchodilators, without the need of inhaled corticosteroids (ICS). The first line of treatment should be just 1 bronchodilator, either a long-acting antimuscarinic (LAMA) or long-actingbeta agonist (LABA). These could be used together as second-line treatment (LAMA plus LABA), still without indication for ICS. It is important to remember that dyspnea, or other symptoms, could also be a manifestation of comorbid conditions, such as cardiovascular disease, obesity, deconditioning, and musculoskeletal diseases.¹³ When spirometry is not used to confirm the diagnosis of COPD, patients may receive incremental types of inhalers instead of being evaluated for other causes of dyspnea, which might have led to more appropriate specific therapy.¹⁴ As a result, judicious evaluation of the patient’s symptomsis recommended. The guidelines also recommend programs that increase physical activity for this group of patients, as well to those in groups C and D, as this can improve symptoms and decrease risk of exacerbations.¹⁵

Group C: High Risk, Low Symptoms

The combination of ICS/LABA is the first-line therapy for this group, based on data showing the superiority of the ICS/LABA combination over monotherapy to reduce exacerbations and symptoms, as well as to improve QOL.^16,17 Monotherapy LABA is also a first-line GOLD recommendation. Selecting between ICS/LABA vs LABA should be individualized based on the reason that the patient was judged as high risk. In the authors’ practice, if
the risk is based only in spirometry values, using LABA as monotherapy is a good choice, while if the definition of high risk was based on the frequency of exacerbations, ICS/LABA is the first choice. The GOLD guidelines list the combination of LABA/LAMA as second-line therapy.

Group D: High Risk and High Symptoms

First-line therapy for this group is essentially the same that for group C, with similar considerations. The combination of LABA/LAMA is also recommended as second-line therapy, as well as the use of ICS/LABA and LAMA (all 3 major classes of controller medications together). It is worth noting that phosphodiesterase-4 inhibitors (PDE4-inh, roflumilast being the best known) can be considered as a third-line of therapy (in group C) or as part of secondline combinations (in group D).

Benefits and Limitations of GOLD

There is no doubt that the new classification system and treatment guidelines are a significant step forward, intended to foster the development of more personalized decisions for COPD patients. The guidelines are the first attempt to incorporate the concepts of phenotypes (frequent exacerbation phenotype), disease heterogeneity (the variation in outcomes for the same degree of airflow obstruction), and the differences between the burden of symptoms and the risk of outcomes. The guidelines incorporate the need to weigh the benefits and risks of medications at the individual level (eg, ICS without an accompanying long-acting agent are not recommended in any group, and ICS use is reserved for those with high risk, especially if the designation is based on exacerbation frequency). The guidelines also stress the importance of examining comorbidities, emphysizing that their management should in no way be altered just because the patient also has COPD. Relative to the previous staging based only on FEV₁ values, this new classification system has been shown to have appropriate predictive ability and association with the risk of exacerbations, and better correlation with measures of quality of life and costs of care.^18,19 The guidelines, initially released in 2011 and slightly updated recently, are in continuous development and have been subject to intense evaluation.

Some limitations have been found (eg, the classification is still not the best predictor of mortality, but has the same ability to predict hospital admission as the previous spirometry-based system).^18,20,21 Hence, it should be no surprise that modifications will likely be released in the near future.

The treatment recommendations associated with the current classification are based on the best evidence available and expert opinion, as no published clinical trials have compared the group-based therapy system to standard therapies. Evaluations of their effectiveness in real-life practice are still to be released. Previous, less complex guidelines, based on spirometry stages, were followed < 60% of the time in actual practice, thus it will be surprising to find high adherence to the current recommendations, but evaluations are still in progress.²²

Conclusion

The best way for primary care providers to incorporate the GOLD guidelines into daily practice is to remember that COPD is very heterogeneous. Although spirometry is important, it is also essential to inquire about exacerbation frequency and symptoms severity. It is encouraging that for each of the relevant questions needed to classify the patient, there is a clear, easy to remember cut point. First, look at symptoms (low or high burden, based on the presence of dyspnea), then to judge risk look at FEV₁ percentage predicted (using 50% as a cutpoint) and at exacerbation frequency (using 2 per year as the cut point). With those simple questions, build the groups, based on the combination of answers, and select the appropriate therapy. The general assumptions are that short-acting medications are appropriate for infrequent symptoms, long-acting medications are used to control symptoms and prevent exacerbations in more severe disease, and that ICS (always in combination with LABA) are reserved for those in the high-risk groups, especially if high risk is defined by frequent exacerbations. This summary should be supplemented with the judicious use of the tables and figures provided in this review, and available with detailed description and discussion in the original sources.¹

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner; Frontline Medical Communications Inc.; the Department of Defense, or its Components; and the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

Asthma and chronic obstructive pulmonary disease (COPD) are common obstructive airway diseases frequently seen by clinicians in practice. Approximately 25 million Americans are reported to have asthma, and 15 million Americans have been diagnosed with COPD.^1,2 An additional 24 million American adults have evidence of impaired lung function, suggestive of an under diagnosis of COPD.³ According to the National Heart, Lung and Blood Institute, the costs of COPD and asthma totaled $68.0 billion in 2008, of which $53.7 billion were direct costs.⁴ A subset of patients with asthma and COPD have characteristics of both disorders and are described clinically as having asthma-COPD overlap syndrome (ACOS).⁵ Patients with ACOS have a higher burden of disease and health care utilization and increasing recognition of this condition is critical. This article will review the identification, epidemiology, diagnostic evaluation, and basic treatment strategy for ACOS. This information should assist the primary care physician (PCP) in his or her approach to this condition.

The distinction between asthma and COPD is usually most evident to the clinician at the extremes of age. Asthma typically develops in childhood, manifests with classic symptoms of recurrent chest tightness, cough, wheeze, and dyspnea, and tends to be associated with atopic disorders. Chronic obstructive pulmonary disease typically manifests later in life, is insidious with productive cough and dyspnea being prominent symptoms, and tends to be associated with tobacco smoking. In addition, asthma is characterized by intermittent, reversible airflow obstruction, whereas COPD has persistent and irreversible airflow obstruction. As such, a nonsmoking atopic younger patient with a history of recurrent childhood wheezing with reversible airflow obstruction would favor a diagnosis of asthma. In contrast, an older patient with a history of tobacco smoking with chronic cough and dyspnea with evidence of fixed obstruction would favor a diagnosis of COPD.

Although asthma and COPD can present “classically,” many clinicians recognize that these disorders may present with overlapping features that make distinguishing between the two diagnostically challenging. Soriano and colleagues succinctly outlined the difficulties in distinguishing between asthma and COPD⁸:

• The conditions are viewed as part of a disease continuum;
• They have strong overlapping features
• There is no incentive to differentiate whether their treatment and prognosis are the same
• There are a lack of clear guidelines as to how the distinction can be made in clinical practice
• Uncertain criteria are used by physicians to classify patients as having asthma or COPD

The term ACOS is a clinical descriptive one and has not been clearly defined as evidenced by the multitude of descriptions in the literature. Soler-Cataluña and colleagues defined the clinical phenotype as “overlap phenotype COPD-asthma” based on the presence of major and minor criteria.⁹ Major criteria consisted of a postbronchodilator increase of forced expiratory volume in 1 second (FEV₁) ≥ 12% and ≥ 400 mL, and eosinophilia in sputum in addition to a personal history of asthma. Minor criteria included high total immunoglobulinE (IgE), personal history of atopy, and a postbronchodilator increase of FEV₁ ≥ 12% and ≥ 200 mL on ≥ 2 occasions.

Zeki and colleagues defined ACOS as: (1) asthma with partially reversible airflow obstruction, with or without emphysema or reduced carbon monoxide diffusion capacity (DLCO) to < 80% predicted; and (2) COPD with emphysema accompanied by reversible or partially reversible airflow obstruction, with or without environmental allergies or reduced DLCO.¹⁰ Louie and colleagues proposed the following major criteria for ACOS: a physician diagnosis of asthma and COPD in the same patient, history of evidence of atopy, elevated total IgE, aged ≥ 40 years, smoking > 10 pack-years, postbronchodilator FEV₁< 80% predicted and FEV₁/forced vital capacity (FVC) < 70%.¹¹ Minor criteria consisted of a postbronchodilator increase of FEV₁ by ≥ 15% or ≥ 12% and ≥ 200 mL following albuterol.

The Global Initiative for Asthma/Global Initiative for Chronic Obstructive Lung Disease published a joint consensus document on ACOS, which described a stepwise approach to diagnosis based on defining characteristics.⁵ To distinguish between the diagnosis of asthma, COPD, and ACOS in an adult patient, the guideline focuses on the features that are felt to be most helpful in distinguishing the syndromes in stepwise fashion. The physician should first assemble the features that favor a diagnosis of asthma or COPD, then compare the number of features in favor of a diagnosis of asthma or COPD, and finally consider the level of certainty around the diagnosis of asthma or COPD or whether there are features of both, suggesting ACOS.

Frequency

In 1995, the American Thoracic Society guidelines defined 11 distinct obstructive lung disease syndromes and identified overlap syndromes in 6 of them.¹² Soriano and colleagues quantified the subpopulations of these patients by analyzing the U.S. National Health and Nutrition Examination III survey and the U.K. General Practice Research Database and reported an increased frequency of overlapping diagnosis of asthma and COPD with advancing age, with an estimated prevalence for < 10% in patients aged < 50 years and > 50% in patients aged ≥ 80 years.⁸ A study of patients aged > 50 years by Marsh and colleagues reported a combined syndrome of asthma and COPD to be the most common phenotype as confirmed by spirometry.¹³ In this study, 62% of subjects with the combined asthma and COPD phenotype were current or former smokers. In a study of 44 adults aged > 55 years with stable asthma or COPD, Gibson and colleague reported that 16% and 21%, respectively, could be categorized as having overlap syndrome.¹⁴ As in previous studies, those with overlap syndrome and COPD were predominantly ex-smokers.

Braman and colleagues characterized asthma in subjects aged > 70 years.¹⁵ Compared with those who developed asthma at an advanced age, those with early onset asthma had a significantly greater degree of airflow obstruction on pre- and postbronchodilator testing. This study suggested that long-standing asthma may lead to chronic persistent airflow obstruction and mimic COPD.

A longitudinal study by Vonk and colleagues reported that 16% of patients with asthma had developed incomplete airflow reversibility after 21 to 33 years of followup.¹⁶ De Marco and colleagues found the prevalence of asthma-COPD overlap to be 1.6%, 2.1%, and 4.5% in the 20 to 44, 45 to 64, and 65 to 84 years age groups, respectively, through a screening questionnaire of the general Italian population in concurrence with previous studies, noting an increased prevalence of ACOS in the elderly.¹⁷ Lee and colleagues described those with ACOS as older, male asthmatics, who have a higher lifetime smoking history and generally worse lung function.¹⁸

Quality of Life, Morbidity, and Moratality

In addition to being more prevalent in the elderly, ACOS is associated with more severe symptoms, impairment in quality of life (QOL), more frequent exacerbations, and high health care utilization. The ACOS phenotype is also at risk for accelerated decline in lung function secondary to its association with advancing age, tobacco smoking, presence of bronchial hyper-reactivity, and exacerbations.¹⁴

Burrows and colleagues described the characteristics and course of asthma in subjects aged > 65 years and concluded that asthma in this group may be associated with severe symptoms, higher death rates, and chronic airway obstruction.¹⁹ In this study, the subjects with suspected ACOS smoked at least 20 pack-years and had a significantly lower mean FEV1 (48.1% predicted ± 23.7) than any other group. Kauppi and colleagues reported on health-related QOL (HRQOL) and found that when compared to subjects with asthma or COPD only, the overlap group had the poorest HRQOL score.²⁰ Chung and colleagues reported a similar reduction on self-rated health in the overlap group as well.²¹ Miravitles and colleagues reported that 17.4% of subjects previously diagnosed with COPD belonged to the COPD-asthma overlap phenotype.²² The overlap phenotype in this study had more dyspnea, wheezing, exacerbations, worse respiratory-specific QOL, and reduced levels of physical activity. Soriano and colleagues identified higher relative risks for pneumonia and respiratory infections in individuals aged > 65 years with asthma and COPD.²³ In a study of hospital discharge registry data covering the Finnish population, Andersén and colleagues reported that the average numbers of treatment periods during 2000 to 2009 were 2.1 in asthma, 3.4 in COPD, and 6.0 in ACOS.²⁴ Panizza and colleagues reported that long-standing asthma was associated with chronic airflow obstruction and increased risk of mortality.²⁵

Although patients with both asthma and COPD are at risk for exacerbations, those with ACOS are at risk for more frequent and severe exacerbations.²⁶ In the PLATINO study population, subjects with ACOS had higher risk for exacerbations, hospitalization, and worse general health status when compared with those with COPD.²⁷ Frequent exacerbations of COPD leads to a greater loss of lung function compared with those who have infrequent exacerbations.¹⁴ A lower FEV₁ is associated with increased disease severity in both asthma and COPD, and this is of particular concern to those with ACOS.

Of significance is the association of the ACOS phenotype with tobacco smoking. Although asthma is a risk factor for accelerated lung function decline, smoking status significantly accelerates the decline, and the loss may be even greater in those with asthma who smoke.^28,29 This can ultimately predispose patients to the ACOS phenotype. Fortunately, quitting smoking can slow the decline in lung function as reported in the Lung Health Study.³⁰ The annual decline in FEV₁ in subjects who quit smoking at the beginning of the 11-year study was 30.2 mL /year for men and 21.5 mL /year for women. For those who continued smoking, the decline in FEV₁ was 66.1 mL /year in men and 54.2 mL /year in women. For those with ACOS, treating tobacco use and dependence should be regarded as a primary and specific intervention.

Diagnosis

Spirometry is required for the appropriate diagnosis of obstructive lung disease and should be performed at least annually for assessment of control and disease progression.^5,31,32 Postbronchodilator spirometry is necessary to determine whether obstruction (ie, FEV1/FVC < 0.7), if present, is reversible.³² In asthma, airway obstruction following bronchodilator administration is typically fully reversible.⁵ In COPD, patients will remain obstructed following postbronchodilator administration regardless of the FEV₁ response.³² In ACOS, the postbronchodilator FEV₁/FVC typically remains obstructed.⁵ A normal postbronchodilator FEV₁/FVC is not compatible with the diagnosis of ACOS unless there is other evidence of chronic airflow limitation.⁵ Although spirometry confirms the presence of chronic airflow obstruction, it is of limited value in distinguishing between asthma with fixed airflow obstruction, COPD, and ACOS.⁵ At times, specialized investigations, such as carbon monoxide diffusion capacity on pulmonary function testing and chest imaging, may also be used to help distinguish between asthma and COPD.^5,31,32

Treatment

Although much has been published on the recognition and identification of ACOS, there is a paucity of information on the effectiveness of therapeutics for this population. Patients with ACOS are frequently excluded from clinical studies involving asthma and COPD, which limits the generalization of findings from these trials to these patients. Although a comprehensive review of the available treatments for obstructive airway disease is beyond the scope of this article, some management tenets will be discussed.

In general, inhaled corticosteroids (ICS) are the cornerstone of the pharmacologic management of patients with persistent asthma, whereas inhaled bronchodilators (beta 2-agonists and anticholinergics) are the therapeutic mainstay for patients with COPD.^31,32 In those with ACOS, the default position should be to start treatment with low or moderate dose ICS in recognition of the role of ICS in preventing morbidity and mortality in those with asthma.⁵ Depending on severity, a long-acting beta 2-agonist (LABA) could be added or continued if already prescribed for those with ACOS.⁵ Patients should not be treated with a LABA without ICS if there are features of asthma.⁵

Treatment of ACOS should also include advice about other therapeutic strategies such as smoking cessation, pulmonary rehabilitation, influenza and pneumococcal vaccinations, and treatment of other comorbid conditions.⁵ The treatment goals of ACOS are similar to those of asthma and COPD in that they are driven by controlling symptoms, optimizing health status and QOL, and preventing exacerbations. Although there are currently no disease-modifying medications that can alter the progression of airway obstruction in either asthma or COPD, smoking cessation is an essential component of the successful management of all obstructive airway disorders, because it is a modifiable risk factor.

The initial management of asthma and COPD can be carried out at the primary care level. All current guidelines for asthma, COPD, and ACOS provide
recommendations for specialty referral for further diagnostic and therapeutic consideations.^5,31,32 As ACOS is associated with more severe disease and greater health care utilization, specialty referral for this subgroup should be considered.

Conclusion

Although there is no generally agreed term or defining features for ACOS, it is commonly recognized that a proportion of older patients who present with symptoms of chronic airway obstruction have features of both asthma and COPD. It is broadly recognized that distinguishing asthma from COPD can be problematic, particularly in smokers and the elderly. In addition, as these patients have frequent exacerbations, a poor QOL, a more rapid decline in lung function, and high mortality, identification of this subgroup is important. The lack of clinical trials to help guide therapeutic interventions in this syndrome is problematic as the extrapolation of data from asthma and/or COPD trials may not be applicable. Further studies in therapeutics for those with ACOS are warranted.

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.
 

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner; Frontline Medical Communications Inc.; the Department of Defense, or its Components; and the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

Asthma and chronic obstructive pulmonary disease (COPD) are common obstructive airway diseases frequently seen by clinicians in practice. Approximately 25 million Americans are reported to have asthma, and 15 million Americans have been diagnosed with COPD.^1,2 An additional 24 million American adults have evidence of impaired lung function, suggestive of an under diagnosis of COPD.³ According to the National Heart, Lung and Blood Institute, the costs of COPD and asthma totaled $68.0 billion in 2008, of which $53.7 billion were direct costs.⁴ A subset of patients with asthma and COPD have characteristics of both disorders and are described clinically as having asthma-COPD overlap syndrome (ACOS).⁵ Patients with ACOS have a higher burden of disease and health care utilization and increasing recognition of this condition is critical. This article will review the identification, epidemiology, diagnostic evaluation, and basic treatment strategy for ACOS. This information should assist the primary care physician (PCP) in his or her approach to this condition.

The distinction between asthma and COPD is usually most evident to the clinician at the extremes of age. Asthma typically develops in childhood, manifests with classic symptoms of recurrent chest tightness, cough, wheeze, and dyspnea, and tends to be associated with atopic disorders. Chronic obstructive pulmonary disease typically manifests later in life, is insidious with productive cough and dyspnea being prominent symptoms, and tends to be associated with tobacco smoking. In addition, asthma is characterized by intermittent, reversible airflow obstruction, whereas COPD has persistent and irreversible airflow obstruction. As such, a nonsmoking atopic younger patient with a history of recurrent childhood wheezing with reversible airflow obstruction would favor a diagnosis of asthma. In contrast, an older patient with a history of tobacco smoking with chronic cough and dyspnea with evidence of fixed obstruction would favor a diagnosis of COPD.

Although asthma and COPD can present “classically,” many clinicians recognize that these disorders may present with overlapping features that make distinguishing between the two diagnostically challenging. Soriano and colleagues succinctly outlined the difficulties in distinguishing between asthma and COPD⁸:

• The conditions are viewed as part of a disease continuum;
• They have strong overlapping features
• There is no incentive to differentiate whether their treatment and prognosis are the same
• There are a lack of clear guidelines as to how the distinction can be made in clinical practice
• Uncertain criteria are used by physicians to classify patients as having asthma or COPD

The term ACOS is a clinical descriptive one and has not been clearly defined as evidenced by the multitude of descriptions in the literature. Soler-Cataluña and colleagues defined the clinical phenotype as “overlap phenotype COPD-asthma” based on the presence of major and minor criteria.⁹ Major criteria consisted of a postbronchodilator increase of forced expiratory volume in 1 second (FEV₁) ≥ 12% and ≥ 400 mL, and eosinophilia in sputum in addition to a personal history of asthma. Minor criteria included high total immunoglobulinE (IgE), personal history of atopy, and a postbronchodilator increase of FEV₁ ≥ 12% and ≥ 200 mL on ≥ 2 occasions.

Zeki and colleagues defined ACOS as: (1) asthma with partially reversible airflow obstruction, with or without emphysema or reduced carbon monoxide diffusion capacity (DLCO) to < 80% predicted; and (2) COPD with emphysema accompanied by reversible or partially reversible airflow obstruction, with or without environmental allergies or reduced DLCO.¹⁰ Louie and colleagues proposed the following major criteria for ACOS: a physician diagnosis of asthma and COPD in the same patient, history of evidence of atopy, elevated total IgE, aged ≥ 40 years, smoking > 10 pack-years, postbronchodilator FEV₁< 80% predicted and FEV₁/forced vital capacity (FVC) < 70%.¹¹ Minor criteria consisted of a postbronchodilator increase of FEV₁ by ≥ 15% or ≥ 12% and ≥ 200 mL following albuterol.

The Global Initiative for Asthma/Global Initiative for Chronic Obstructive Lung Disease published a joint consensus document on ACOS, which described a stepwise approach to diagnosis based on defining characteristics.⁵ To distinguish between the diagnosis of asthma, COPD, and ACOS in an adult patient, the guideline focuses on the features that are felt to be most helpful in distinguishing the syndromes in stepwise fashion. The physician should first assemble the features that favor a diagnosis of asthma or COPD, then compare the number of features in favor of a diagnosis of asthma or COPD, and finally consider the level of certainty around the diagnosis of asthma or COPD or whether there are features of both, suggesting ACOS.

Frequency

In 1995, the American Thoracic Society guidelines defined 11 distinct obstructive lung disease syndromes and identified overlap syndromes in 6 of them.¹² Soriano and colleagues quantified the subpopulations of these patients by analyzing the U.S. National Health and Nutrition Examination III survey and the U.K. General Practice Research Database and reported an increased frequency of overlapping diagnosis of asthma and COPD with advancing age, with an estimated prevalence for < 10% in patients aged < 50 years and > 50% in patients aged ≥ 80 years.⁸ A study of patients aged > 50 years by Marsh and colleagues reported a combined syndrome of asthma and COPD to be the most common phenotype as confirmed by spirometry.¹³ In this study, 62% of subjects with the combined asthma and COPD phenotype were current or former smokers. In a study of 44 adults aged > 55 years with stable asthma or COPD, Gibson and colleague reported that 16% and 21%, respectively, could be categorized as having overlap syndrome.¹⁴ As in previous studies, those with overlap syndrome and COPD were predominantly ex-smokers.

Braman and colleagues characterized asthma in subjects aged > 70 years.¹⁵ Compared with those who developed asthma at an advanced age, those with early onset asthma had a significantly greater degree of airflow obstruction on pre- and postbronchodilator testing. This study suggested that long-standing asthma may lead to chronic persistent airflow obstruction and mimic COPD.

A longitudinal study by Vonk and colleagues reported that 16% of patients with asthma had developed incomplete airflow reversibility after 21 to 33 years of followup.¹⁶ De Marco and colleagues found the prevalence of asthma-COPD overlap to be 1.6%, 2.1%, and 4.5% in the 20 to 44, 45 to 64, and 65 to 84 years age groups, respectively, through a screening questionnaire of the general Italian population in concurrence with previous studies, noting an increased prevalence of ACOS in the elderly.¹⁷ Lee and colleagues described those with ACOS as older, male asthmatics, who have a higher lifetime smoking history and generally worse lung function.¹⁸

Quality of Life, Morbidity, and Moratality

In addition to being more prevalent in the elderly, ACOS is associated with more severe symptoms, impairment in quality of life (QOL), more frequent exacerbations, and high health care utilization. The ACOS phenotype is also at risk for accelerated decline in lung function secondary to its association with advancing age, tobacco smoking, presence of bronchial hyper-reactivity, and exacerbations.¹⁴

Burrows and colleagues described the characteristics and course of asthma in subjects aged > 65 years and concluded that asthma in this group may be associated with severe symptoms, higher death rates, and chronic airway obstruction.¹⁹ In this study, the subjects with suspected ACOS smoked at least 20 pack-years and had a significantly lower mean FEV1 (48.1% predicted ± 23.7) than any other group. Kauppi and colleagues reported on health-related QOL (HRQOL) and found that when compared to subjects with asthma or COPD only, the overlap group had the poorest HRQOL score.²⁰ Chung and colleagues reported a similar reduction on self-rated health in the overlap group as well.²¹ Miravitles and colleagues reported that 17.4% of subjects previously diagnosed with COPD belonged to the COPD-asthma overlap phenotype.²² The overlap phenotype in this study had more dyspnea, wheezing, exacerbations, worse respiratory-specific QOL, and reduced levels of physical activity. Soriano and colleagues identified higher relative risks for pneumonia and respiratory infections in individuals aged > 65 years with asthma and COPD.²³ In a study of hospital discharge registry data covering the Finnish population, Andersén and colleagues reported that the average numbers of treatment periods during 2000 to 2009 were 2.1 in asthma, 3.4 in COPD, and 6.0 in ACOS.²⁴ Panizza and colleagues reported that long-standing asthma was associated with chronic airflow obstruction and increased risk of mortality.²⁵

Although patients with both asthma and COPD are at risk for exacerbations, those with ACOS are at risk for more frequent and severe exacerbations.²⁶ In the PLATINO study population, subjects with ACOS had higher risk for exacerbations, hospitalization, and worse general health status when compared with those with COPD.²⁷ Frequent exacerbations of COPD leads to a greater loss of lung function compared with those who have infrequent exacerbations.¹⁴ A lower FEV₁ is associated with increased disease severity in both asthma and COPD, and this is of particular concern to those with ACOS.

Of significance is the association of the ACOS phenotype with tobacco smoking. Although asthma is a risk factor for accelerated lung function decline, smoking status significantly accelerates the decline, and the loss may be even greater in those with asthma who smoke.^28,29 This can ultimately predispose patients to the ACOS phenotype. Fortunately, quitting smoking can slow the decline in lung function as reported in the Lung Health Study.³⁰ The annual decline in FEV₁ in subjects who quit smoking at the beginning of the 11-year study was 30.2 mL /year for men and 21.5 mL /year for women. For those who continued smoking, the decline in FEV₁ was 66.1 mL /year in men and 54.2 mL /year in women. For those with ACOS, treating tobacco use and dependence should be regarded as a primary and specific intervention.

Diagnosis

Spirometry is required for the appropriate diagnosis of obstructive lung disease and should be performed at least annually for assessment of control and disease progression.^5,31,32 Postbronchodilator spirometry is necessary to determine whether obstruction (ie, FEV1/FVC < 0.7), if present, is reversible.³² In asthma, airway obstruction following bronchodilator administration is typically fully reversible.⁵ In COPD, patients will remain obstructed following postbronchodilator administration regardless of the FEV₁ response.³² In ACOS, the postbronchodilator FEV₁/FVC typically remains obstructed.⁵ A normal postbronchodilator FEV₁/FVC is not compatible with the diagnosis of ACOS unless there is other evidence of chronic airflow limitation.⁵ Although spirometry confirms the presence of chronic airflow obstruction, it is of limited value in distinguishing between asthma with fixed airflow obstruction, COPD, and ACOS.⁵ At times, specialized investigations, such as carbon monoxide diffusion capacity on pulmonary function testing and chest imaging, may also be used to help distinguish between asthma and COPD.^5,31,32

Treatment

Although much has been published on the recognition and identification of ACOS, there is a paucity of information on the effectiveness of therapeutics for this population. Patients with ACOS are frequently excluded from clinical studies involving asthma and COPD, which limits the generalization of findings from these trials to these patients. Although a comprehensive review of the available treatments for obstructive airway disease is beyond the scope of this article, some management tenets will be discussed.

In general, inhaled corticosteroids (ICS) are the cornerstone of the pharmacologic management of patients with persistent asthma, whereas inhaled bronchodilators (beta 2-agonists and anticholinergics) are the therapeutic mainstay for patients with COPD.^31,32 In those with ACOS, the default position should be to start treatment with low or moderate dose ICS in recognition of the role of ICS in preventing morbidity and mortality in those with asthma.⁵ Depending on severity, a long-acting beta 2-agonist (LABA) could be added or continued if already prescribed for those with ACOS.⁵ Patients should not be treated with a LABA without ICS if there are features of asthma.⁵

Treatment of ACOS should also include advice about other therapeutic strategies such as smoking cessation, pulmonary rehabilitation, influenza and pneumococcal vaccinations, and treatment of other comorbid conditions.⁵ The treatment goals of ACOS are similar to those of asthma and COPD in that they are driven by controlling symptoms, optimizing health status and QOL, and preventing exacerbations. Although there are currently no disease-modifying medications that can alter the progression of airway obstruction in either asthma or COPD, smoking cessation is an essential component of the successful management of all obstructive airway disorders, because it is a modifiable risk factor.

The initial management of asthma and COPD can be carried out at the primary care level. All current guidelines for asthma, COPD, and ACOS provide
recommendations for specialty referral for further diagnostic and therapeutic consideations.^5,31,32 As ACOS is associated with more severe disease and greater health care utilization, specialty referral for this subgroup should be considered.

Conclusion

Although there is no generally agreed term or defining features for ACOS, it is commonly recognized that a proportion of older patients who present with symptoms of chronic airway obstruction have features of both asthma and COPD. It is broadly recognized that distinguishing asthma from COPD can be problematic, particularly in smokers and the elderly. In addition, as these patients have frequent exacerbations, a poor QOL, a more rapid decline in lung function, and high mortality, identification of this subgroup is important. The lack of clinical trials to help guide therapeutic interventions in this syndrome is problematic as the extrapolation of data from asthma and/or COPD trials may not be applicable. Further studies in therapeutics for those with ACOS are warranted.

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.
 

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner; Frontline Medical Communications Inc.; the Department of Defense, or its Components; and the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

Asthma and chronic obstructive pulmonary disease (COPD) are common obstructive airway diseases frequently seen by clinicians in practice. Approximately 25 million Americans are reported to have asthma, and 15 million Americans have been diagnosed with COPD.^1,2 An additional 24 million American adults have evidence of impaired lung function, suggestive of an under diagnosis of COPD.³ According to the National Heart, Lung and Blood Institute, the costs of COPD and asthma totaled $68.0 billion in 2008, of which $53.7 billion were direct costs.⁴ A subset of patients with asthma and COPD have characteristics of both disorders and are described clinically as having asthma-COPD overlap syndrome (ACOS).⁵ Patients with ACOS have a higher burden of disease and health care utilization and increasing recognition of this condition is critical. This article will review the identification, epidemiology, diagnostic evaluation, and basic treatment strategy for ACOS. This information should assist the primary care physician (PCP) in his or her approach to this condition.

The distinction between asthma and COPD is usually most evident to the clinician at the extremes of age. Asthma typically develops in childhood, manifests with classic symptoms of recurrent chest tightness, cough, wheeze, and dyspnea, and tends to be associated with atopic disorders. Chronic obstructive pulmonary disease typically manifests later in life, is insidious with productive cough and dyspnea being prominent symptoms, and tends to be associated with tobacco smoking. In addition, asthma is characterized by intermittent, reversible airflow obstruction, whereas COPD has persistent and irreversible airflow obstruction. As such, a nonsmoking atopic younger patient with a history of recurrent childhood wheezing with reversible airflow obstruction would favor a diagnosis of asthma. In contrast, an older patient with a history of tobacco smoking with chronic cough and dyspnea with evidence of fixed obstruction would favor a diagnosis of COPD.

Although asthma and COPD can present “classically,” many clinicians recognize that these disorders may present with overlapping features that make distinguishing between the two diagnostically challenging. Soriano and colleagues succinctly outlined the difficulties in distinguishing between asthma and COPD⁸:

• The conditions are viewed as part of a disease continuum;
• They have strong overlapping features
• There is no incentive to differentiate whether their treatment and prognosis are the same
• There are a lack of clear guidelines as to how the distinction can be made in clinical practice
• Uncertain criteria are used by physicians to classify patients as having asthma or COPD

The term ACOS is a clinical descriptive one and has not been clearly defined as evidenced by the multitude of descriptions in the literature. Soler-Cataluña and colleagues defined the clinical phenotype as “overlap phenotype COPD-asthma” based on the presence of major and minor criteria.⁹ Major criteria consisted of a postbronchodilator increase of forced expiratory volume in 1 second (FEV₁) ≥ 12% and ≥ 400 mL, and eosinophilia in sputum in addition to a personal history of asthma. Minor criteria included high total immunoglobulinE (IgE), personal history of atopy, and a postbronchodilator increase of FEV₁ ≥ 12% and ≥ 200 mL on ≥ 2 occasions.

Zeki and colleagues defined ACOS as: (1) asthma with partially reversible airflow obstruction, with or without emphysema or reduced carbon monoxide diffusion capacity (DLCO) to < 80% predicted; and (2) COPD with emphysema accompanied by reversible or partially reversible airflow obstruction, with or without environmental allergies or reduced DLCO.¹⁰ Louie and colleagues proposed the following major criteria for ACOS: a physician diagnosis of asthma and COPD in the same patient, history of evidence of atopy, elevated total IgE, aged ≥ 40 years, smoking > 10 pack-years, postbronchodilator FEV₁< 80% predicted and FEV₁/forced vital capacity (FVC) < 70%.¹¹ Minor criteria consisted of a postbronchodilator increase of FEV₁ by ≥ 15% or ≥ 12% and ≥ 200 mL following albuterol.

The Global Initiative for Asthma/Global Initiative for Chronic Obstructive Lung Disease published a joint consensus document on ACOS, which described a stepwise approach to diagnosis based on defining characteristics.⁵ To distinguish between the diagnosis of asthma, COPD, and ACOS in an adult patient, the guideline focuses on the features that are felt to be most helpful in distinguishing the syndromes in stepwise fashion. The physician should first assemble the features that favor a diagnosis of asthma or COPD, then compare the number of features in favor of a diagnosis of asthma or COPD, and finally consider the level of certainty around the diagnosis of asthma or COPD or whether there are features of both, suggesting ACOS.

Frequency

In 1995, the American Thoracic Society guidelines defined 11 distinct obstructive lung disease syndromes and identified overlap syndromes in 6 of them.¹² Soriano and colleagues quantified the subpopulations of these patients by analyzing the U.S. National Health and Nutrition Examination III survey and the U.K. General Practice Research Database and reported an increased frequency of overlapping diagnosis of asthma and COPD with advancing age, with an estimated prevalence for < 10% in patients aged < 50 years and > 50% in patients aged ≥ 80 years.⁸ A study of patients aged > 50 years by Marsh and colleagues reported a combined syndrome of asthma and COPD to be the most common phenotype as confirmed by spirometry.¹³ In this study, 62% of subjects with the combined asthma and COPD phenotype were current or former smokers. In a study of 44 adults aged > 55 years with stable asthma or COPD, Gibson and colleague reported that 16% and 21%, respectively, could be categorized as having overlap syndrome.¹⁴ As in previous studies, those with overlap syndrome and COPD were predominantly ex-smokers.

Braman and colleagues characterized asthma in subjects aged > 70 years.¹⁵ Compared with those who developed asthma at an advanced age, those with early onset asthma had a significantly greater degree of airflow obstruction on pre- and postbronchodilator testing. This study suggested that long-standing asthma may lead to chronic persistent airflow obstruction and mimic COPD.

A longitudinal study by Vonk and colleagues reported that 16% of patients with asthma had developed incomplete airflow reversibility after 21 to 33 years of followup.¹⁶ De Marco and colleagues found the prevalence of asthma-COPD overlap to be 1.6%, 2.1%, and 4.5% in the 20 to 44, 45 to 64, and 65 to 84 years age groups, respectively, through a screening questionnaire of the general Italian population in concurrence with previous studies, noting an increased prevalence of ACOS in the elderly.¹⁷ Lee and colleagues described those with ACOS as older, male asthmatics, who have a higher lifetime smoking history and generally worse lung function.¹⁸

Quality of Life, Morbidity, and Moratality

In addition to being more prevalent in the elderly, ACOS is associated with more severe symptoms, impairment in quality of life (QOL), more frequent exacerbations, and high health care utilization. The ACOS phenotype is also at risk for accelerated decline in lung function secondary to its association with advancing age, tobacco smoking, presence of bronchial hyper-reactivity, and exacerbations.¹⁴

Burrows and colleagues described the characteristics and course of asthma in subjects aged > 65 years and concluded that asthma in this group may be associated with severe symptoms, higher death rates, and chronic airway obstruction.¹⁹ In this study, the subjects with suspected ACOS smoked at least 20 pack-years and had a significantly lower mean FEV1 (48.1% predicted ± 23.7) than any other group. Kauppi and colleagues reported on health-related QOL (HRQOL) and found that when compared to subjects with asthma or COPD only, the overlap group had the poorest HRQOL score.²⁰ Chung and colleagues reported a similar reduction on self-rated health in the overlap group as well.²¹ Miravitles and colleagues reported that 17.4% of subjects previously diagnosed with COPD belonged to the COPD-asthma overlap phenotype.²² The overlap phenotype in this study had more dyspnea, wheezing, exacerbations, worse respiratory-specific QOL, and reduced levels of physical activity. Soriano and colleagues identified higher relative risks for pneumonia and respiratory infections in individuals aged > 65 years with asthma and COPD.²³ In a study of hospital discharge registry data covering the Finnish population, Andersén and colleagues reported that the average numbers of treatment periods during 2000 to 2009 were 2.1 in asthma, 3.4 in COPD, and 6.0 in ACOS.²⁴ Panizza and colleagues reported that long-standing asthma was associated with chronic airflow obstruction and increased risk of mortality.²⁵

Although patients with both asthma and COPD are at risk for exacerbations, those with ACOS are at risk for more frequent and severe exacerbations.²⁶ In the PLATINO study population, subjects with ACOS had higher risk for exacerbations, hospitalization, and worse general health status when compared with those with COPD.²⁷ Frequent exacerbations of COPD leads to a greater loss of lung function compared with those who have infrequent exacerbations.¹⁴ A lower FEV₁ is associated with increased disease severity in both asthma and COPD, and this is of particular concern to those with ACOS.

Of significance is the association of the ACOS phenotype with tobacco smoking. Although asthma is a risk factor for accelerated lung function decline, smoking status significantly accelerates the decline, and the loss may be even greater in those with asthma who smoke.^28,29 This can ultimately predispose patients to the ACOS phenotype. Fortunately, quitting smoking can slow the decline in lung function as reported in the Lung Health Study.³⁰ The annual decline in FEV₁ in subjects who quit smoking at the beginning of the 11-year study was 30.2 mL /year for men and 21.5 mL /year for women. For those who continued smoking, the decline in FEV₁ was 66.1 mL /year in men and 54.2 mL /year in women. For those with ACOS, treating tobacco use and dependence should be regarded as a primary and specific intervention.

Diagnosis

Spirometry is required for the appropriate diagnosis of obstructive lung disease and should be performed at least annually for assessment of control and disease progression.^5,31,32 Postbronchodilator spirometry is necessary to determine whether obstruction (ie, FEV1/FVC < 0.7), if present, is reversible.³² In asthma, airway obstruction following bronchodilator administration is typically fully reversible.⁵ In COPD, patients will remain obstructed following postbronchodilator administration regardless of the FEV₁ response.³² In ACOS, the postbronchodilator FEV₁/FVC typically remains obstructed.⁵ A normal postbronchodilator FEV₁/FVC is not compatible with the diagnosis of ACOS unless there is other evidence of chronic airflow limitation.⁵ Although spirometry confirms the presence of chronic airflow obstruction, it is of limited value in distinguishing between asthma with fixed airflow obstruction, COPD, and ACOS.⁵ At times, specialized investigations, such as carbon monoxide diffusion capacity on pulmonary function testing and chest imaging, may also be used to help distinguish between asthma and COPD.^5,31,32

Treatment

Although much has been published on the recognition and identification of ACOS, there is a paucity of information on the effectiveness of therapeutics for this population. Patients with ACOS are frequently excluded from clinical studies involving asthma and COPD, which limits the generalization of findings from these trials to these patients. Although a comprehensive review of the available treatments for obstructive airway disease is beyond the scope of this article, some management tenets will be discussed.

In general, inhaled corticosteroids (ICS) are the cornerstone of the pharmacologic management of patients with persistent asthma, whereas inhaled bronchodilators (beta 2-agonists and anticholinergics) are the therapeutic mainstay for patients with COPD.^31,32 In those with ACOS, the default position should be to start treatment with low or moderate dose ICS in recognition of the role of ICS in preventing morbidity and mortality in those with asthma.⁵ Depending on severity, a long-acting beta 2-agonist (LABA) could be added or continued if already prescribed for those with ACOS.⁵ Patients should not be treated with a LABA without ICS if there are features of asthma.⁵

Treatment of ACOS should also include advice about other therapeutic strategies such as smoking cessation, pulmonary rehabilitation, influenza and pneumococcal vaccinations, and treatment of other comorbid conditions.⁵ The treatment goals of ACOS are similar to those of asthma and COPD in that they are driven by controlling symptoms, optimizing health status and QOL, and preventing exacerbations. Although there are currently no disease-modifying medications that can alter the progression of airway obstruction in either asthma or COPD, smoking cessation is an essential component of the successful management of all obstructive airway disorders, because it is a modifiable risk factor.

The initial management of asthma and COPD can be carried out at the primary care level. All current guidelines for asthma, COPD, and ACOS provide
recommendations for specialty referral for further diagnostic and therapeutic consideations.^5,31,32 As ACOS is associated with more severe disease and greater health care utilization, specialty referral for this subgroup should be considered.

Conclusion

Although there is no generally agreed term or defining features for ACOS, it is commonly recognized that a proportion of older patients who present with symptoms of chronic airway obstruction have features of both asthma and COPD. It is broadly recognized that distinguishing asthma from COPD can be problematic, particularly in smokers and the elderly. In addition, as these patients have frequent exacerbations, a poor QOL, a more rapid decline in lung function, and high mortality, identification of this subgroup is important. The lack of clinical trials to help guide therapeutic interventions in this syndrome is problematic as the extrapolation of data from asthma and/or COPD trials may not be applicable. Further studies in therapeutics for those with ACOS are warranted.

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.
 

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner; Frontline Medical Communications Inc.; the Department of Defense, or its Components; and the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.