In Being Wrong,¹ her treatise on the psychology of human error, Kathryn Schulz quotes William James: “Our errors are surely not such awfully solemn things.”² Being wrong, she argues, is part of the human genome. Despite aphorisms such as “we learn from our mistakes,” we are far from accepting of mistakes in medical practice. Perhaps naively, I do not believe that our need to understand how clinical errors occur and how to avoid them is based on the fear of legal repercussion. And of course we do not want to harm our patients. But our relationship with medical errors is far more complex than that. We really don’t want to be wrong.

Dr. Atul Gawande³ has promoted using checklists and a structured system to limit errors of misapplication of knowledge. Diagnostic and therapeutic algorithms, once the province of trauma surgeons, are increasingly becoming part of internal medicine.

When I was a house officer we all had our “pocket brains” in our white coats—lists of disease complications, drug doses and interactions, causes of IgA deposition in the kidney, and treatment algorithms. But we believed (probably correctly) that our teachers expected us to commit all these facts to memory in our fleshy brains. The elitist and hubristic belief that this was uniformly possible has lingered in academic medicine, still permeating even the fabric of certification examinations. We learn that it is OK to be honest and say that we don’t know the answer, but we don’t like to have to say it. Physicians finish the academic game of Chutes and Ladders with a strong aversion to being wrong.

Younger doctors today seem more comfortable with not knowing so many facts and bits of medical trivia, being able to find answers instantly using their smart phones. But a challenge is knowing at a glance the context and veracity of the answers you find. And whether the knowledge comes from our anatomic, pocket, or cyber brain, the overarching challenge is to avoid Gawande’s error of misapplication.

In this issue of the Journal, Dr. Nikhil Mull and colleagues dissect a clinical case that did not proceed as expected. They discuss, in reference to the described patient, some of the published analyses of the clinical decision-making process, highlighting various ways that our reasoning can be led astray. Having just finished a stint on the inpatient consultation service, I wish I could have read the article a few weeks ago. A bit of reflection on how we reach decisions can be as powerful as knowing the source of the facts in our pocket brain.

Being wrong, as Schulz has written, is part of the human experience, but I don’t like it. Ways to limit the chances of it’s happening in the clinic are worth keeping on a personal checklist, or perhaps as an app on my smart phone.

In Being Wrong,¹ her treatise on the psychology of human error, Kathryn Schulz quotes William James: “Our errors are surely not such awfully solemn things.”² Being wrong, she argues, is part of the human genome. Despite aphorisms such as “we learn from our mistakes,” we are far from accepting of mistakes in medical practice. Perhaps naively, I do not believe that our need to understand how clinical errors occur and how to avoid them is based on the fear of legal repercussion. And of course we do not want to harm our patients. But our relationship with medical errors is far more complex than that. We really don’t want to be wrong.

Dr. Atul Gawande³ has promoted using checklists and a structured system to limit errors of misapplication of knowledge. Diagnostic and therapeutic algorithms, once the province of trauma surgeons, are increasingly becoming part of internal medicine.

When I was a house officer we all had our “pocket brains” in our white coats—lists of disease complications, drug doses and interactions, causes of IgA deposition in the kidney, and treatment algorithms. But we believed (probably correctly) that our teachers expected us to commit all these facts to memory in our fleshy brains. The elitist and hubristic belief that this was uniformly possible has lingered in academic medicine, still permeating even the fabric of certification examinations. We learn that it is OK to be honest and say that we don’t know the answer, but we don’t like to have to say it. Physicians finish the academic game of Chutes and Ladders with a strong aversion to being wrong.

Younger doctors today seem more comfortable with not knowing so many facts and bits of medical trivia, being able to find answers instantly using their smart phones. But a challenge is knowing at a glance the context and veracity of the answers you find. And whether the knowledge comes from our anatomic, pocket, or cyber brain, the overarching challenge is to avoid Gawande’s error of misapplication.

In this issue of the Journal, Dr. Nikhil Mull and colleagues dissect a clinical case that did not proceed as expected. They discuss, in reference to the described patient, some of the published analyses of the clinical decision-making process, highlighting various ways that our reasoning can be led astray. Having just finished a stint on the inpatient consultation service, I wish I could have read the article a few weeks ago. A bit of reflection on how we reach decisions can be as powerful as knowing the source of the facts in our pocket brain.

Being wrong, as Schulz has written, is part of the human experience, but I don’t like it. Ways to limit the chances of it’s happening in the clinic are worth keeping on a personal checklist, or perhaps as an app on my smart phone.

In Being Wrong,¹ her treatise on the psychology of human error, Kathryn Schulz quotes William James: “Our errors are surely not such awfully solemn things.”² Being wrong, she argues, is part of the human genome. Despite aphorisms such as “we learn from our mistakes,” we are far from accepting of mistakes in medical practice. Perhaps naively, I do not believe that our need to understand how clinical errors occur and how to avoid them is based on the fear of legal repercussion. And of course we do not want to harm our patients. But our relationship with medical errors is far more complex than that. We really don’t want to be wrong.

Dr. Atul Gawande³ has promoted using checklists and a structured system to limit errors of misapplication of knowledge. Diagnostic and therapeutic algorithms, once the province of trauma surgeons, are increasingly becoming part of internal medicine.

When I was a house officer we all had our “pocket brains” in our white coats—lists of disease complications, drug doses and interactions, causes of IgA deposition in the kidney, and treatment algorithms. But we believed (probably correctly) that our teachers expected us to commit all these facts to memory in our fleshy brains. The elitist and hubristic belief that this was uniformly possible has lingered in academic medicine, still permeating even the fabric of certification examinations. We learn that it is OK to be honest and say that we don’t know the answer, but we don’t like to have to say it. Physicians finish the academic game of Chutes and Ladders with a strong aversion to being wrong.

Younger doctors today seem more comfortable with not knowing so many facts and bits of medical trivia, being able to find answers instantly using their smart phones. But a challenge is knowing at a glance the context and veracity of the answers you find. And whether the knowledge comes from our anatomic, pocket, or cyber brain, the overarching challenge is to avoid Gawande’s error of misapplication.

In this issue of the Journal, Dr. Nikhil Mull and colleagues dissect a clinical case that did not proceed as expected. They discuss, in reference to the described patient, some of the published analyses of the clinical decision-making process, highlighting various ways that our reasoning can be led astray. Having just finished a stint on the inpatient consultation service, I wish I could have read the article a few weeks ago. A bit of reflection on how we reach decisions can be as powerful as knowing the source of the facts in our pocket brain.

Being wrong, as Schulz has written, is part of the human experience, but I don’t like it. Ways to limit the chances of it’s happening in the clinic are worth keeping on a personal checklist, or perhaps as an app on my smart phone.

An elderly Spanish-speaking woman with morbid obesity, diabetes, hypertension, and rheumatoid arthritis presents to the emergency department with worsening shortness of breath and cough. She speaks only Spanish, so her son provides the history without the aid of an interpreter.

Her shortness of breath is most noticeable with exertion and has increased gradually over the past 2 months. She has a nonproductive cough. Her son has noticed decreased oral intake and weight loss over the past few weeks.  She has neither traveled recently nor been in contact with anyone known to have an infectious disease.

A review of systems is otherwise negative: specifically, she denies chest pain, fevers, or chills. She saw her primary care physician 3 weeks ago for these complaints and was prescribed a 3-day course of azithromycin with no improvement.

Her medications include lisinopril, atenolol, glipizide, and metformin; her son believes she may be taking others as well but is not sure. He is also unsure of what treatment his mother has received for her rheumatoid arthritis, and most of her medical records are within another health system.

The patient’s son believes she may be taking other medications but is not sure; her records are at another institution

On physical examination, the patient is coughing and appears ill. Her temperature is 99.9°F (37.7°C), heart rate 105 beats per minute, blood pressure 140/70 mm Hg, res­piratory rate 24 per minute, and oxygen saturation by pulse oximetry 89% on room air. Heart sounds are normal, jugular venous pressure cannot be assessed because of her obese body habitus, pulmonary examination demonstrates crackles in all lung fields, and lower-extremity edema is not present. Her extremities are warm and well perfused. Musculoskeletal examination reveals deformities of the joints in both hands consistent with rheumatoid arthritis.

Laboratory data:

• White blood cell count 13.0 × 10⁹/L (reference range 3.7–11.0)
• Hemoglobin level 10 g/dL (11.5–15)
• Serum creatinine 1.0 mg/dL (0.7–1.4)
• Pro-brain-type natriuretic peptide (pro-BNP) level greater than the upper limit of normal.

A chest radiograph is obtained, and the resident radiologist’s preliminary impression is that it is consistent with pulmonary vascular congestion.

The patient is admitted for further diagnostic evaluation. The emergency department resident orders intravenous furosemide and signs out to the night float medicine resident that this is an “elderly woman with hypertension, diabetes, and heart failure being admitted for a heart failure exacerbation.”

What is the accuracy of a physician’s initial working diagnosis?

Diagnostic accuracy requires both clinical knowledge and problem-solving skills.¹

A decade ago, a National Patient Safety Foundation survey² found that one in six patients had suffered a medical error related to misdiagnosis. In a large systematic review of autopsy-based diagnostic errors, the theorized rate of major errors ranged from 8.4% to as high as 24.4%.³ A study by Neale et al⁴ found that admitting diagnoses were incorrect in 6% of cases. In emergency departments, inaccuracy rates of up to 12% have been described.⁵

What factors influence the prevalence of diagnostic errors?

Initial empiric treatments, such as intravenous furosemide in the above scenario, add to the challenge of diagnosis in acute care settings and can influence clinical decisions made by subsequent providers.⁶

Nonspecific or vague symptoms make diagnosis especially challenging. Shortness of breath, for example, is a common chief complaint in medical patients, as in this case. Green et al⁷ found emergency department physicians reported clinical uncertainty for a diagnosis of heart failure in 31% of patients evaluated for “dyspnea.” Pulmonary embolism and pulmonary tuberculosis are also in the differential diagnosis for our patient, with studies reporting a misdiagnosis rate of 55% for pulmonary embolism⁸ and 50% for pulmonary tuberculosis.⁹

Hertwig et al,¹⁰ describing the diagnostic process in patients presenting to emergency departments with a nonspecific constellation of symptoms, found particularly low rates of agreement between the initial diagnostic impression and the final, correct one. In fact, the actual diagnosis was only in the physician’s initial “top three” differential diagnoses 29% to 83% of the time.

Atypical presentations of common diseases, initial nonspecific presentations of common diseases, and confounding comorbid conditions have also been associated with misdiagnosis.¹¹ Our case scenario illustrates the frequent challenges physicians face when diagnosing patients who present with nonspecific symptoms and signs on a background of multiple, chronic comorbidities.

Contextual factors in the system and environment contribute to the potential for error.¹² Examples include frequent interruptions, time pressure, poor handoffs, insufficient data, and multitasking.

In our scenario, incomplete data, time constraints, and multitasking in a busy work environment compelled the emergency department resident to rapidly synthesize information to establish a working diagnosis. Interpretations of radiographs by on-call radiology residents are similarly at risk of diagnostic error for the same reasons.¹³

Physician factors also influence diagnosis. Interestingly, physician certainty or uncertainty at the time of initial diagnosis does not uniformly appear to correlate with diagnostic accuracy. A recent study showed that physician confidence remained high regardless of the degree of difficulty in a given case, and degree of confidence also correlated poorly with whether the physician’s diagnosis was accurate.¹⁴

For patients admitted with a chief complaint of dyspnea, as in our scenario, Zwaan et al¹⁵ showed that “inappropriate selectivity” in reasoning contributed to an inaccurate diagnosis 23% of the time. Inappropriate selectivity, as defined by these authors, occurs when a probable diagnosis is not sufficiently considered and therefore is neither confirmed nor ruled out.

In our patient scenario, the failure to consider diagnoses other than heart failure and the inability to confirm a prior diagnosis of heart failure in the emergency department may contribute to a diagnostic error.

CASE CONTINUED: NO IMPROVEMENT OVER 3 DAYS

The night float resident, who has six other admissions this night, cannot ask the resident who evaluated this patient in the emergency department for further information because the shift has ended. The patient’s son left at the time of admission and is not available when the patient arrives on the medical ward.

The night float resident quickly examines the patient, enters admission orders, and signs the patient out to the intern and resident who will be caring for her during her hospitalization. The verbal handoff notes that the history was limited due to a language barrier. The initial problem list includes heart failure without a differential diagnosis, but notes that an elevated pro-BNP and chest radiograph confirm heart failure as the likely diagnosis.

Several hours after the night float resident has left, the resident presents this history to the attending physician, and together they decide to order her regular at-home medications, as well as deep vein thrombosis prophylaxis and echocardiography. In writing the orders, subcutaneous heparin once daily is erroneously entered instead of low-molecular-weight heparin daily, as this is the default in the medical record system. The tired resident fails to recognize this, and the pharmacist does not question it.

Over the next 2 days, the patient’s cough and shortness of breath persist.

After the attending physician dismisses their concerns, the residents do not bring up their idea again

On hospital day 3, two junior residents on the team (who finished their internship 2 weeks ago) review the attending radiologist’s interpretation of the chest radiograph. Unflagged, it confirms the resident’s interpretation but notes ill-defined, scattered, faint opacities. The residents believe that an interstitial pattern may be present and suggest that the patient may not have heart failure but rather a primary pulmonary disease. They bring this to the attention of their attending physician, who dismisses their concerns and comments that heart failure is a clinical diagnosis. The residents do not bring this idea up again to the attending physician.

That night, the float team is called by the nursing staff because of worsening oxygenation and cough. They add an intravenous corticosteroid, a broad-spectrum antibiotic, and an inhaled bronchodilator to the patient’s drug regimen.

How do cognitive errors predispose physicians to diagnostic errors?

When errors in diagnosis are reviewed retrospectively, cognitive or “thinking” errors are generally found, especially in nonprocedural or primary care specialties such as internal medicine, pediatrics, and emergency medicine.^16,17

A widely accepted theory on how humans make decisions was described by the psychologists Tversky and Kahneman in 1974¹⁸ and has been applied more recently to physicians’ diagnostic processes.¹⁹ Their dual process model theory states that persons with a requisite level of expertise use either the intuitive “system 1” process of thinking, based on pattern-recognition and heuristics, or the slower, more analytical “system 2” process.²⁰ Experts disagree as to whether in medicine these processes represent a binary either-or model or a continuum²¹ with relative contributions of each process determined by the physician and the task.

What are some common types of cognitive error?

Experts agree that many diagnostic errors in medicine stem from decisions arrived at by inappropriate system 1 thinking due to biases. These biases have been identified and described as they relate to medicine, most notably by Croskerry.²²

Several cognitive biases are illustrated in our clinical scenario:

The framing effect occurred when the emergency department resident listed the patient’s admitting diagnosis as heart failure during the clinical handoff of care.

Anchoring bias, as defined by Croskerry,²² is the tendency to lock onto salient features of the case too early in the diagnostic process and then to fail to adjust this initial diagnostic impression. This bias affected the admitting night float resident, primary intern, resident, and attending physician.

Diagnostic momentum, in turn, is a well-described phenomenon that clinical providers are especially vulnerable to in today’s environment of “copy-and-paste” medical records and numerous handovers of care as a consequence of residency duty-hour restrictions.²³

Availability bias refers to commonly seen diagnoses like heart failure or recently seen diagnoses, which are more “available” to the human memory. These diagnoses, which spring to mind quickly, often trick providers into thinking that because they are more easily recalled, they are also more common or more likely.

Confirmation bias. The initial working diagnosis of heart failure may have led the medical team to place greater emphasis on the elevated pro-BNP and the chest radiograph to support the initial impression while ignoring findings such as weight loss that do not support this impression.

Blind obedience. Although the residents recognized the possibility of a primary pulmonary disease, they did not investigate this further. And when the attending physician dismissed their suggestion, they thus deferred to the person in authority or with a reputation of expertise.

Overconfidence bias. Despite minimal improvement in the patient’s clinical status after effective diuresis and the suggestion of alternative diagnoses by the residents, the attending physician remained confident—perhaps overconfident—in the diagnosis of heart failure and would not consider alternatives. Overconfidence bias has been well described and occurs when a medical provider believes too strongly in his or her ability to be correct and therefore fails to consider alternative diagnoses.²⁴

Despite succumbing to overconfidence bias, the attending physician was able to overcome base-rate neglect, ie, failure to consider the prevalence of potential diagnoses in diagnostic reasoning.

Each of these biases, and others not mentioned, can lead to premature closure, which is the unfortunate root cause of many diagnostic errors and delays. We have illustrated several biases in our case scenario that led several physicians on the medical team to prematurely “close” on the diagnosis of heart failure (Table 1).

CASE CONTINUED: SURPRISES AND REASSESSMENT

On hospital day 4, the patient’s medication lists from her previous hospitalizations arrive, and the team is surprised to discover that she has been receiving infliximab for the past 3 to 4 months for her rheumatoid arthritis.

Additionally, an echocardiogram that was ordered on hospital day 1 but was lost in the cardiologist’s reading queue comes in and shows a normal ejection fraction with no evidence of elevated filling pressures.

Computed tomography of the chest reveals a reticular pattern with innumerable, tiny, 1- to 2-mm pulmonary nodules. The differential diagnosis is expanded to include hypersensitivity pneumonitis, lymphoma, fungal infection, and miliary tuberculosis.

How do faulty systems contribute to diagnostic error?

It is increasingly recognized that diagnostic errors can occur as a result of cognitive error, systems-based error, or quite commonly, both. Graber et al¹⁷ analyzed 100 cases of diagnostic error and determined that while cognitive errors did occur in most of them, nearly half the time both cognitive and systems-based errors contributed simultaneously.¹⁷ Observers have further delineated the importance of the systems context and how it affects our thinking.²⁵

In this case, the language barrier, lack of availability of family, and inability to promptly utilize interpreter services contributed to early problems in acquiring a detailed history and a complete medication list that included the immunosuppressant infliximab. Later, a systems error led to a delay in the interpretation of an echocardiogram. Each of these factors, if prevented, would have presumably resulted in expansion of the differential diagnosis and earlier arrival at the correct diagnosis.

CASE CONTINUED: THE PATIENT DIES OF TUBERCULOSIS

The patient is moved to a negative pressure room, and the pulmonary consultants recommend bronchoscopy. During the procedure, the patient suffers acute respiratory failure, is intubated, and is transferred to the medical intensive care unit, where a saddle pulmonary embolism is diagnosed by computed tomographic angiography.

One day later, the sputum culture from the bronchoscopy returns as positive for acid-fast bacilli. A four-drug regimen for tuberculosis is started. The patient continues to have a downward course and expires 2 weeks later. Autopsy reveals miliary tuberculosis.

What is the frequency of diagnostic error in medicine?

Diagnostic error is estimated to have a frequency of 10% to 20%.²⁴ Rates of diagnostic error are similar irrespective of method of determination, eg, from autopsy,³ standardized patients (ie, actors presenting with scripted scenarios),²⁶ or case reviews.²⁷ Patient surveys report patient-perceived harm from diagnostic error at a rate of 35% to 42%.^28,29 The landmark Harvard Medical Practice Study found that 17% of all adverse events were attributable to diagnostic error.³⁰

Diagnostic error is the most common type of medical error in nonprocedural medical fields.³¹ It causes a disproportionately large amount of morbidity and death.

Diagnostic error is the most common cause of malpractice claims in the United States. In inpatient and outpatient settings, for both medical and surgical patients, it accounted for 45.9% of all outpatient malpractice claims in 2009, making it the most common reason for medical malpractice litigation.³² A 2013 study indicated that diagnostic error is more common, more expensive, and two times more likely to result in death than any other category of error.³³

CASE CONTINUED: MORBIDITY AND MORTALITY CONFERENCE

The patient’s case is brought to a morbidity and mortality conference for discussion. The systems issues in the case—including medication reconciliation, availability of interpreters, and timing and process of echocardiogram readings—are all discussed, but clinical reasoning and cognitive errors made in the case are avoided.

Why are cognitive errors often neglected in discussions of medical error?

Historically, openly discussing error in medicine has been difficult. Over the past decade, however, and fueled by the landmark Institute of Medicine report To Err is Human,³⁴ the healthcare community has made substantial strides in identifying and talking about systems factors as a cause of preventable medical error.^34,35

While systems contributions to medical error are inherently “external” to physicians and other healthcare providers, the cognitive contributions to error are inherently “internal” and are often considered personal. This has led to diagnostic error being kept out of many patient safety conversations. Further, while the solutions to systems errors are often tangible, such as implementing a fall prevention program or changing the physical packaging of a medication to reduce a medication dispensing or administration error, solutions to cognitive errors are generally considered more challenging to address by organizations trying to improve patient safety.

How can hospitals and department leaders do better?

Healthcare organizations and leaders of clinical teams or departments can implement several strategies.³⁶

First, they can seek out and analyze the causes of diagnostic errors that are occurring locally in their institution and learn from their diagnostic errors, such as the one in our clinical scenario.

Trainees, physicians, and nurses should be comfortable questioning each other

Second, they can promote a culture of open communication and questioning around diagnosis. Trainees, physicians, and nurses should be comfortable questioning each other, including those higher up in the hierarchy, by saying, “I’m not sure” or “What else could this be?” to help reduce cognitive bias and expand the diagnostic possibilities.

Similarly, developing strategies to promote feedback on diagnosis among physicians will allow us all to learn from our diagnostic mistakes.

Use of the electronic medical record to assist in follow-up of pending diagnostic studies and patient return visits is yet another strategy.

Finally, healthcare organizations can adopt strategies to promote patient involvement in diagnosis, such as providing patients with copies of their test results and discharge summaries, encouraging the use of electronic patient communication portals, and empowering patients to ask questions related to their diagnosis. Prioritizing potential solutions to reduce diagnostic errors may be helpful in situations, depending on the context and environment, in which all proposed interventions may not be possible.

CASE CONTINUED: LEARNING FROM MISTAKES

The attending physician and resident in the case meet after the conference to review their clinical decision-making. Both are interested in learning from this case and improving their diagnostic skills in the future.

What specific steps can clinicians take to mitigate cognitive bias in daily practice?

In addition to continuing to expand one’s medical knowledge and gain more clinical experience, we can suggest several small steps to busy clinicians, taken individually or in combination with others that may improve diagnostic skills by reducing the potential for biased thinking in clinical practice.

From Croskerry P. Clinical cognition and diagnostic error: applications of a dual process model of reasoning. Adv Health Sci Educ 2009; 14:27–35. With kind permission from Springer Science and Business Media.

Think about your thinking. Our first recommendation would be to become more familiar with the dual process theory of clinical cognition (Figure 1).^37,38 This theoretical framework may be very helpful as a foundation from which to build better thinking skills. Physicians, especially residents, and students can be taught these concepts and their potential to contribute to diagnostic errors, and can use these skills to recognize those contributions in others’ diagnostic practices and even in their own.³⁹

Facilitating metacognition, or “thinking about one’s thinking,” may help clinicians catch themselves in thinking traps and provide the opportunity to reflect on biases retrospectively, as a double check or an opportunity to learn from a mistake.

Recognize your emotions. Gaining an understanding of the effect of one’s emotions on decision-making also can help clinicians free themselves of bias. As human beings, healthcare professionals are  susceptible to emotion, and the best approach to mitigate the emotional influences may be to consciously name them and adjust for them.⁴⁰

Because it is impractical to apply slow, analytical system 2 approaches to every case, skills that hone and develop more accurate, reliable system 1 thinking are crucial. Gaining broad exposure to increased numbers of cases may be the most reliable way to build an experiential repertoire of “illness scripts,” but there are ways to increase the experiential value of any case with a few techniques that have potential to promote better intuition.⁴¹

Embracing uncertainty in the early diagnostic process and envisioning the worst-case scenario in a case allows the consideration of additional diagnostic paths outside of the current working diagnosis, potentially priming the clinician to look for and recognize early warning signs that could argue against the initial diagnosis at a time when an adjustment could be made to prevent a bad outcome.

Practice progressive problem-solving,⁴² a technique in which the physician creates additional challenges to increase the cognitive burden of a “routine” case in an effort to train his or her mind and sharpen intuition. An example of this practice is contemplating a backup treatment plan in advance in the event of a poor response to or an adverse effect of treatment. Highly rated physicians and teachers perform this regularly.^43,44 Other ways to maximize the learning value of an individual case include seeking feedback on patient outcomes, especially when a patient has been discharged or transferred to another provider’s care, or when the physician goes off service.

Simulation, traditionally used for procedural training, has potential as well. Cognitive simulation, such as case reports or virtual patient modules, have potential to enhance clinical reasoning skills as well, though possibly at greater cost of time and expense.

Decreased reliance on memory is likely to improve diagnostic reasoning. Systems tools such as checklists⁴⁵ and health information technology⁴⁶ have potential to reduce diagnostic errors, not by taking thinking away from the clinician but by relieving the cognitive load enough to facilitate greater effort toward reasoning.

Slow down. Finally, and perhaps most important, recent models of clinical expertise have suggested that mastery comes from having a robust intuitive method, with a sense of the limitations of the intuitive approach, an ability to recognize the need to perform more analytical reasoning in select cases, and the willingness to do so. In short, it may well be that the hallmark of a master clinician is the propensity to slow down when necessary.⁴⁷

A ‘diagnostic time-out’ for safety might catch opportunities to recognize and mitigate biases and errors

If one considers diagnosis a cognitive procedure, perhaps a brief “diagnostic time-out” for safety might afford an opportunity to recognize and mitigate biases and errors. There are likely many potential scripts for a good diagnostic time-out, but to be functional it should be brief and simple to facilitate consistent use. We have recommended the following four questions to our residents as a starting point, any of which could signal the need to switch to a slower, analytic approach.

Four-step diagnostic time-out

• What else can it be?
• Is there anything about the case that does not fit?
• Is it possible that multiple processes are going on?
• Do I need to slow down?

These questions can serve as a double check for an intuitively formed initial working diagnosis, incorporating many of the principles discussed above, in a way that would hopefully avoid undue burden on a busy clinician. These techniques, it must be acknowledged, have not yet been directly tied to reductions in diagnostic errors. However, diagnostic errors, as discussed, are very difficult to identify and study, and these techniques will serve mainly to improve habits that are likely to show benefits over much longer time periods than most studies can measure.

An elderly Spanish-speaking woman with morbid obesity, diabetes, hypertension, and rheumatoid arthritis presents to the emergency department with worsening shortness of breath and cough. She speaks only Spanish, so her son provides the history without the aid of an interpreter.

Her shortness of breath is most noticeable with exertion and has increased gradually over the past 2 months. She has a nonproductive cough. Her son has noticed decreased oral intake and weight loss over the past few weeks.  She has neither traveled recently nor been in contact with anyone known to have an infectious disease.

A review of systems is otherwise negative: specifically, she denies chest pain, fevers, or chills. She saw her primary care physician 3 weeks ago for these complaints and was prescribed a 3-day course of azithromycin with no improvement.

Her medications include lisinopril, atenolol, glipizide, and metformin; her son believes she may be taking others as well but is not sure. He is also unsure of what treatment his mother has received for her rheumatoid arthritis, and most of her medical records are within another health system.

The patient’s son believes she may be taking other medications but is not sure; her records are at another institution

On physical examination, the patient is coughing and appears ill. Her temperature is 99.9°F (37.7°C), heart rate 105 beats per minute, blood pressure 140/70 mm Hg, res­piratory rate 24 per minute, and oxygen saturation by pulse oximetry 89% on room air. Heart sounds are normal, jugular venous pressure cannot be assessed because of her obese body habitus, pulmonary examination demonstrates crackles in all lung fields, and lower-extremity edema is not present. Her extremities are warm and well perfused. Musculoskeletal examination reveals deformities of the joints in both hands consistent with rheumatoid arthritis.

Laboratory data:

• White blood cell count 13.0 × 10⁹/L (reference range 3.7–11.0)
• Hemoglobin level 10 g/dL (11.5–15)
• Serum creatinine 1.0 mg/dL (0.7–1.4)
• Pro-brain-type natriuretic peptide (pro-BNP) level greater than the upper limit of normal.

A chest radiograph is obtained, and the resident radiologist’s preliminary impression is that it is consistent with pulmonary vascular congestion.

The patient is admitted for further diagnostic evaluation. The emergency department resident orders intravenous furosemide and signs out to the night float medicine resident that this is an “elderly woman with hypertension, diabetes, and heart failure being admitted for a heart failure exacerbation.”

What is the accuracy of a physician’s initial working diagnosis?

Diagnostic accuracy requires both clinical knowledge and problem-solving skills.¹

A decade ago, a National Patient Safety Foundation survey² found that one in six patients had suffered a medical error related to misdiagnosis. In a large systematic review of autopsy-based diagnostic errors, the theorized rate of major errors ranged from 8.4% to as high as 24.4%.³ A study by Neale et al⁴ found that admitting diagnoses were incorrect in 6% of cases. In emergency departments, inaccuracy rates of up to 12% have been described.⁵

What factors influence the prevalence of diagnostic errors?

Initial empiric treatments, such as intravenous furosemide in the above scenario, add to the challenge of diagnosis in acute care settings and can influence clinical decisions made by subsequent providers.⁶

Nonspecific or vague symptoms make diagnosis especially challenging. Shortness of breath, for example, is a common chief complaint in medical patients, as in this case. Green et al⁷ found emergency department physicians reported clinical uncertainty for a diagnosis of heart failure in 31% of patients evaluated for “dyspnea.” Pulmonary embolism and pulmonary tuberculosis are also in the differential diagnosis for our patient, with studies reporting a misdiagnosis rate of 55% for pulmonary embolism⁸ and 50% for pulmonary tuberculosis.⁹

Hertwig et al,¹⁰ describing the diagnostic process in patients presenting to emergency departments with a nonspecific constellation of symptoms, found particularly low rates of agreement between the initial diagnostic impression and the final, correct one. In fact, the actual diagnosis was only in the physician’s initial “top three” differential diagnoses 29% to 83% of the time.

Atypical presentations of common diseases, initial nonspecific presentations of common diseases, and confounding comorbid conditions have also been associated with misdiagnosis.¹¹ Our case scenario illustrates the frequent challenges physicians face when diagnosing patients who present with nonspecific symptoms and signs on a background of multiple, chronic comorbidities.

Contextual factors in the system and environment contribute to the potential for error.¹² Examples include frequent interruptions, time pressure, poor handoffs, insufficient data, and multitasking.

In our scenario, incomplete data, time constraints, and multitasking in a busy work environment compelled the emergency department resident to rapidly synthesize information to establish a working diagnosis. Interpretations of radiographs by on-call radiology residents are similarly at risk of diagnostic error for the same reasons.¹³

Physician factors also influence diagnosis. Interestingly, physician certainty or uncertainty at the time of initial diagnosis does not uniformly appear to correlate with diagnostic accuracy. A recent study showed that physician confidence remained high regardless of the degree of difficulty in a given case, and degree of confidence also correlated poorly with whether the physician’s diagnosis was accurate.¹⁴

For patients admitted with a chief complaint of dyspnea, as in our scenario, Zwaan et al¹⁵ showed that “inappropriate selectivity” in reasoning contributed to an inaccurate diagnosis 23% of the time. Inappropriate selectivity, as defined by these authors, occurs when a probable diagnosis is not sufficiently considered and therefore is neither confirmed nor ruled out.

In our patient scenario, the failure to consider diagnoses other than heart failure and the inability to confirm a prior diagnosis of heart failure in the emergency department may contribute to a diagnostic error.

CASE CONTINUED: NO IMPROVEMENT OVER 3 DAYS

The night float resident, who has six other admissions this night, cannot ask the resident who evaluated this patient in the emergency department for further information because the shift has ended. The patient’s son left at the time of admission and is not available when the patient arrives on the medical ward.

The night float resident quickly examines the patient, enters admission orders, and signs the patient out to the intern and resident who will be caring for her during her hospitalization. The verbal handoff notes that the history was limited due to a language barrier. The initial problem list includes heart failure without a differential diagnosis, but notes that an elevated pro-BNP and chest radiograph confirm heart failure as the likely diagnosis.

Several hours after the night float resident has left, the resident presents this history to the attending physician, and together they decide to order her regular at-home medications, as well as deep vein thrombosis prophylaxis and echocardiography. In writing the orders, subcutaneous heparin once daily is erroneously entered instead of low-molecular-weight heparin daily, as this is the default in the medical record system. The tired resident fails to recognize this, and the pharmacist does not question it.

Over the next 2 days, the patient’s cough and shortness of breath persist.

After the attending physician dismisses their concerns, the residents do not bring up their idea again

On hospital day 3, two junior residents on the team (who finished their internship 2 weeks ago) review the attending radiologist’s interpretation of the chest radiograph. Unflagged, it confirms the resident’s interpretation but notes ill-defined, scattered, faint opacities. The residents believe that an interstitial pattern may be present and suggest that the patient may not have heart failure but rather a primary pulmonary disease. They bring this to the attention of their attending physician, who dismisses their concerns and comments that heart failure is a clinical diagnosis. The residents do not bring this idea up again to the attending physician.

That night, the float team is called by the nursing staff because of worsening oxygenation and cough. They add an intravenous corticosteroid, a broad-spectrum antibiotic, and an inhaled bronchodilator to the patient’s drug regimen.

How do cognitive errors predispose physicians to diagnostic errors?

When errors in diagnosis are reviewed retrospectively, cognitive or “thinking” errors are generally found, especially in nonprocedural or primary care specialties such as internal medicine, pediatrics, and emergency medicine.^16,17

A widely accepted theory on how humans make decisions was described by the psychologists Tversky and Kahneman in 1974¹⁸ and has been applied more recently to physicians’ diagnostic processes.¹⁹ Their dual process model theory states that persons with a requisite level of expertise use either the intuitive “system 1” process of thinking, based on pattern-recognition and heuristics, or the slower, more analytical “system 2” process.²⁰ Experts disagree as to whether in medicine these processes represent a binary either-or model or a continuum²¹ with relative contributions of each process determined by the physician and the task.

What are some common types of cognitive error?

Experts agree that many diagnostic errors in medicine stem from decisions arrived at by inappropriate system 1 thinking due to biases. These biases have been identified and described as they relate to medicine, most notably by Croskerry.²²

Several cognitive biases are illustrated in our clinical scenario:

The framing effect occurred when the emergency department resident listed the patient’s admitting diagnosis as heart failure during the clinical handoff of care.

Anchoring bias, as defined by Croskerry,²² is the tendency to lock onto salient features of the case too early in the diagnostic process and then to fail to adjust this initial diagnostic impression. This bias affected the admitting night float resident, primary intern, resident, and attending physician.

Diagnostic momentum, in turn, is a well-described phenomenon that clinical providers are especially vulnerable to in today’s environment of “copy-and-paste” medical records and numerous handovers of care as a consequence of residency duty-hour restrictions.²³

Availability bias refers to commonly seen diagnoses like heart failure or recently seen diagnoses, which are more “available” to the human memory. These diagnoses, which spring to mind quickly, often trick providers into thinking that because they are more easily recalled, they are also more common or more likely.

Confirmation bias. The initial working diagnosis of heart failure may have led the medical team to place greater emphasis on the elevated pro-BNP and the chest radiograph to support the initial impression while ignoring findings such as weight loss that do not support this impression.

Blind obedience. Although the residents recognized the possibility of a primary pulmonary disease, they did not investigate this further. And when the attending physician dismissed their suggestion, they thus deferred to the person in authority or with a reputation of expertise.

Overconfidence bias. Despite minimal improvement in the patient’s clinical status after effective diuresis and the suggestion of alternative diagnoses by the residents, the attending physician remained confident—perhaps overconfident—in the diagnosis of heart failure and would not consider alternatives. Overconfidence bias has been well described and occurs when a medical provider believes too strongly in his or her ability to be correct and therefore fails to consider alternative diagnoses.²⁴

Despite succumbing to overconfidence bias, the attending physician was able to overcome base-rate neglect, ie, failure to consider the prevalence of potential diagnoses in diagnostic reasoning.

Each of these biases, and others not mentioned, can lead to premature closure, which is the unfortunate root cause of many diagnostic errors and delays. We have illustrated several biases in our case scenario that led several physicians on the medical team to prematurely “close” on the diagnosis of heart failure (Table 1).

CASE CONTINUED: SURPRISES AND REASSESSMENT

On hospital day 4, the patient’s medication lists from her previous hospitalizations arrive, and the team is surprised to discover that she has been receiving infliximab for the past 3 to 4 months for her rheumatoid arthritis.

Additionally, an echocardiogram that was ordered on hospital day 1 but was lost in the cardiologist’s reading queue comes in and shows a normal ejection fraction with no evidence of elevated filling pressures.

Computed tomography of the chest reveals a reticular pattern with innumerable, tiny, 1- to 2-mm pulmonary nodules. The differential diagnosis is expanded to include hypersensitivity pneumonitis, lymphoma, fungal infection, and miliary tuberculosis.

How do faulty systems contribute to diagnostic error?

It is increasingly recognized that diagnostic errors can occur as a result of cognitive error, systems-based error, or quite commonly, both. Graber et al¹⁷ analyzed 100 cases of diagnostic error and determined that while cognitive errors did occur in most of them, nearly half the time both cognitive and systems-based errors contributed simultaneously.¹⁷ Observers have further delineated the importance of the systems context and how it affects our thinking.²⁵

In this case, the language barrier, lack of availability of family, and inability to promptly utilize interpreter services contributed to early problems in acquiring a detailed history and a complete medication list that included the immunosuppressant infliximab. Later, a systems error led to a delay in the interpretation of an echocardiogram. Each of these factors, if prevented, would have presumably resulted in expansion of the differential diagnosis and earlier arrival at the correct diagnosis.

CASE CONTINUED: THE PATIENT DIES OF TUBERCULOSIS

The patient is moved to a negative pressure room, and the pulmonary consultants recommend bronchoscopy. During the procedure, the patient suffers acute respiratory failure, is intubated, and is transferred to the medical intensive care unit, where a saddle pulmonary embolism is diagnosed by computed tomographic angiography.

One day later, the sputum culture from the bronchoscopy returns as positive for acid-fast bacilli. A four-drug regimen for tuberculosis is started. The patient continues to have a downward course and expires 2 weeks later. Autopsy reveals miliary tuberculosis.

What is the frequency of diagnostic error in medicine?

Diagnostic error is estimated to have a frequency of 10% to 20%.²⁴ Rates of diagnostic error are similar irrespective of method of determination, eg, from autopsy,³ standardized patients (ie, actors presenting with scripted scenarios),²⁶ or case reviews.²⁷ Patient surveys report patient-perceived harm from diagnostic error at a rate of 35% to 42%.^28,29 The landmark Harvard Medical Practice Study found that 17% of all adverse events were attributable to diagnostic error.³⁰

Diagnostic error is the most common type of medical error in nonprocedural medical fields.³¹ It causes a disproportionately large amount of morbidity and death.

Diagnostic error is the most common cause of malpractice claims in the United States. In inpatient and outpatient settings, for both medical and surgical patients, it accounted for 45.9% of all outpatient malpractice claims in 2009, making it the most common reason for medical malpractice litigation.³² A 2013 study indicated that diagnostic error is more common, more expensive, and two times more likely to result in death than any other category of error.³³

CASE CONTINUED: MORBIDITY AND MORTALITY CONFERENCE

The patient’s case is brought to a morbidity and mortality conference for discussion. The systems issues in the case—including medication reconciliation, availability of interpreters, and timing and process of echocardiogram readings—are all discussed, but clinical reasoning and cognitive errors made in the case are avoided.

Why are cognitive errors often neglected in discussions of medical error?

Historically, openly discussing error in medicine has been difficult. Over the past decade, however, and fueled by the landmark Institute of Medicine report To Err is Human,³⁴ the healthcare community has made substantial strides in identifying and talking about systems factors as a cause of preventable medical error.^34,35

While systems contributions to medical error are inherently “external” to physicians and other healthcare providers, the cognitive contributions to error are inherently “internal” and are often considered personal. This has led to diagnostic error being kept out of many patient safety conversations. Further, while the solutions to systems errors are often tangible, such as implementing a fall prevention program or changing the physical packaging of a medication to reduce a medication dispensing or administration error, solutions to cognitive errors are generally considered more challenging to address by organizations trying to improve patient safety.

How can hospitals and department leaders do better?

Healthcare organizations and leaders of clinical teams or departments can implement several strategies.³⁶

First, they can seek out and analyze the causes of diagnostic errors that are occurring locally in their institution and learn from their diagnostic errors, such as the one in our clinical scenario.

Trainees, physicians, and nurses should be comfortable questioning each other

Second, they can promote a culture of open communication and questioning around diagnosis. Trainees, physicians, and nurses should be comfortable questioning each other, including those higher up in the hierarchy, by saying, “I’m not sure” or “What else could this be?” to help reduce cognitive bias and expand the diagnostic possibilities.

Similarly, developing strategies to promote feedback on diagnosis among physicians will allow us all to learn from our diagnostic mistakes.

Use of the electronic medical record to assist in follow-up of pending diagnostic studies and patient return visits is yet another strategy.

Finally, healthcare organizations can adopt strategies to promote patient involvement in diagnosis, such as providing patients with copies of their test results and discharge summaries, encouraging the use of electronic patient communication portals, and empowering patients to ask questions related to their diagnosis. Prioritizing potential solutions to reduce diagnostic errors may be helpful in situations, depending on the context and environment, in which all proposed interventions may not be possible.

CASE CONTINUED: LEARNING FROM MISTAKES

The attending physician and resident in the case meet after the conference to review their clinical decision-making. Both are interested in learning from this case and improving their diagnostic skills in the future.

What specific steps can clinicians take to mitigate cognitive bias in daily practice?

In addition to continuing to expand one’s medical knowledge and gain more clinical experience, we can suggest several small steps to busy clinicians, taken individually or in combination with others that may improve diagnostic skills by reducing the potential for biased thinking in clinical practice.

From Croskerry P. Clinical cognition and diagnostic error: applications of a dual process model of reasoning. Adv Health Sci Educ 2009; 14:27–35. With kind permission from Springer Science and Business Media.

Think about your thinking. Our first recommendation would be to become more familiar with the dual process theory of clinical cognition (Figure 1).^37,38 This theoretical framework may be very helpful as a foundation from which to build better thinking skills. Physicians, especially residents, and students can be taught these concepts and their potential to contribute to diagnostic errors, and can use these skills to recognize those contributions in others’ diagnostic practices and even in their own.³⁹

Facilitating metacognition, or “thinking about one’s thinking,” may help clinicians catch themselves in thinking traps and provide the opportunity to reflect on biases retrospectively, as a double check or an opportunity to learn from a mistake.

Recognize your emotions. Gaining an understanding of the effect of one’s emotions on decision-making also can help clinicians free themselves of bias. As human beings, healthcare professionals are  susceptible to emotion, and the best approach to mitigate the emotional influences may be to consciously name them and adjust for them.⁴⁰

Because it is impractical to apply slow, analytical system 2 approaches to every case, skills that hone and develop more accurate, reliable system 1 thinking are crucial. Gaining broad exposure to increased numbers of cases may be the most reliable way to build an experiential repertoire of “illness scripts,” but there are ways to increase the experiential value of any case with a few techniques that have potential to promote better intuition.⁴¹

Embracing uncertainty in the early diagnostic process and envisioning the worst-case scenario in a case allows the consideration of additional diagnostic paths outside of the current working diagnosis, potentially priming the clinician to look for and recognize early warning signs that could argue against the initial diagnosis at a time when an adjustment could be made to prevent a bad outcome.

Practice progressive problem-solving,⁴² a technique in which the physician creates additional challenges to increase the cognitive burden of a “routine” case in an effort to train his or her mind and sharpen intuition. An example of this practice is contemplating a backup treatment plan in advance in the event of a poor response to or an adverse effect of treatment. Highly rated physicians and teachers perform this regularly.^43,44 Other ways to maximize the learning value of an individual case include seeking feedback on patient outcomes, especially when a patient has been discharged or transferred to another provider’s care, or when the physician goes off service.

Simulation, traditionally used for procedural training, has potential as well. Cognitive simulation, such as case reports or virtual patient modules, have potential to enhance clinical reasoning skills as well, though possibly at greater cost of time and expense.

Decreased reliance on memory is likely to improve diagnostic reasoning. Systems tools such as checklists⁴⁵ and health information technology⁴⁶ have potential to reduce diagnostic errors, not by taking thinking away from the clinician but by relieving the cognitive load enough to facilitate greater effort toward reasoning.

Slow down. Finally, and perhaps most important, recent models of clinical expertise have suggested that mastery comes from having a robust intuitive method, with a sense of the limitations of the intuitive approach, an ability to recognize the need to perform more analytical reasoning in select cases, and the willingness to do so. In short, it may well be that the hallmark of a master clinician is the propensity to slow down when necessary.⁴⁷

A ‘diagnostic time-out’ for safety might catch opportunities to recognize and mitigate biases and errors

If one considers diagnosis a cognitive procedure, perhaps a brief “diagnostic time-out” for safety might afford an opportunity to recognize and mitigate biases and errors. There are likely many potential scripts for a good diagnostic time-out, but to be functional it should be brief and simple to facilitate consistent use. We have recommended the following four questions to our residents as a starting point, any of which could signal the need to switch to a slower, analytic approach.

Four-step diagnostic time-out

• What else can it be?
• Is there anything about the case that does not fit?
• Is it possible that multiple processes are going on?
• Do I need to slow down?

These questions can serve as a double check for an intuitively formed initial working diagnosis, incorporating many of the principles discussed above, in a way that would hopefully avoid undue burden on a busy clinician. These techniques, it must be acknowledged, have not yet been directly tied to reductions in diagnostic errors. However, diagnostic errors, as discussed, are very difficult to identify and study, and these techniques will serve mainly to improve habits that are likely to show benefits over much longer time periods than most studies can measure.

An elderly Spanish-speaking woman with morbid obesity, diabetes, hypertension, and rheumatoid arthritis presents to the emergency department with worsening shortness of breath and cough. She speaks only Spanish, so her son provides the history without the aid of an interpreter.

Her shortness of breath is most noticeable with exertion and has increased gradually over the past 2 months. She has a nonproductive cough. Her son has noticed decreased oral intake and weight loss over the past few weeks.  She has neither traveled recently nor been in contact with anyone known to have an infectious disease.

A review of systems is otherwise negative: specifically, she denies chest pain, fevers, or chills. She saw her primary care physician 3 weeks ago for these complaints and was prescribed a 3-day course of azithromycin with no improvement.

Her medications include lisinopril, atenolol, glipizide, and metformin; her son believes she may be taking others as well but is not sure. He is also unsure of what treatment his mother has received for her rheumatoid arthritis, and most of her medical records are within another health system.

The patient’s son believes she may be taking other medications but is not sure; her records are at another institution

On physical examination, the patient is coughing and appears ill. Her temperature is 99.9°F (37.7°C), heart rate 105 beats per minute, blood pressure 140/70 mm Hg, res­piratory rate 24 per minute, and oxygen saturation by pulse oximetry 89% on room air. Heart sounds are normal, jugular venous pressure cannot be assessed because of her obese body habitus, pulmonary examination demonstrates crackles in all lung fields, and lower-extremity edema is not present. Her extremities are warm and well perfused. Musculoskeletal examination reveals deformities of the joints in both hands consistent with rheumatoid arthritis.

Laboratory data:

• White blood cell count 13.0 × 10⁹/L (reference range 3.7–11.0)
• Hemoglobin level 10 g/dL (11.5–15)
• Serum creatinine 1.0 mg/dL (0.7–1.4)
• Pro-brain-type natriuretic peptide (pro-BNP) level greater than the upper limit of normal.

A chest radiograph is obtained, and the resident radiologist’s preliminary impression is that it is consistent with pulmonary vascular congestion.

The patient is admitted for further diagnostic evaluation. The emergency department resident orders intravenous furosemide and signs out to the night float medicine resident that this is an “elderly woman with hypertension, diabetes, and heart failure being admitted for a heart failure exacerbation.”

What is the accuracy of a physician’s initial working diagnosis?

Diagnostic accuracy requires both clinical knowledge and problem-solving skills.¹

A decade ago, a National Patient Safety Foundation survey² found that one in six patients had suffered a medical error related to misdiagnosis. In a large systematic review of autopsy-based diagnostic errors, the theorized rate of major errors ranged from 8.4% to as high as 24.4%.³ A study by Neale et al⁴ found that admitting diagnoses were incorrect in 6% of cases. In emergency departments, inaccuracy rates of up to 12% have been described.⁵

What factors influence the prevalence of diagnostic errors?

Initial empiric treatments, such as intravenous furosemide in the above scenario, add to the challenge of diagnosis in acute care settings and can influence clinical decisions made by subsequent providers.⁶

Nonspecific or vague symptoms make diagnosis especially challenging. Shortness of breath, for example, is a common chief complaint in medical patients, as in this case. Green et al⁷ found emergency department physicians reported clinical uncertainty for a diagnosis of heart failure in 31% of patients evaluated for “dyspnea.” Pulmonary embolism and pulmonary tuberculosis are also in the differential diagnosis for our patient, with studies reporting a misdiagnosis rate of 55% for pulmonary embolism⁸ and 50% for pulmonary tuberculosis.⁹

Hertwig et al,¹⁰ describing the diagnostic process in patients presenting to emergency departments with a nonspecific constellation of symptoms, found particularly low rates of agreement between the initial diagnostic impression and the final, correct one. In fact, the actual diagnosis was only in the physician’s initial “top three” differential diagnoses 29% to 83% of the time.

Atypical presentations of common diseases, initial nonspecific presentations of common diseases, and confounding comorbid conditions have also been associated with misdiagnosis.¹¹ Our case scenario illustrates the frequent challenges physicians face when diagnosing patients who present with nonspecific symptoms and signs on a background of multiple, chronic comorbidities.

Contextual factors in the system and environment contribute to the potential for error.¹² Examples include frequent interruptions, time pressure, poor handoffs, insufficient data, and multitasking.

In our scenario, incomplete data, time constraints, and multitasking in a busy work environment compelled the emergency department resident to rapidly synthesize information to establish a working diagnosis. Interpretations of radiographs by on-call radiology residents are similarly at risk of diagnostic error for the same reasons.¹³

Physician factors also influence diagnosis. Interestingly, physician certainty or uncertainty at the time of initial diagnosis does not uniformly appear to correlate with diagnostic accuracy. A recent study showed that physician confidence remained high regardless of the degree of difficulty in a given case, and degree of confidence also correlated poorly with whether the physician’s diagnosis was accurate.¹⁴

For patients admitted with a chief complaint of dyspnea, as in our scenario, Zwaan et al¹⁵ showed that “inappropriate selectivity” in reasoning contributed to an inaccurate diagnosis 23% of the time. Inappropriate selectivity, as defined by these authors, occurs when a probable diagnosis is not sufficiently considered and therefore is neither confirmed nor ruled out.

In our patient scenario, the failure to consider diagnoses other than heart failure and the inability to confirm a prior diagnosis of heart failure in the emergency department may contribute to a diagnostic error.

CASE CONTINUED: NO IMPROVEMENT OVER 3 DAYS

The night float resident, who has six other admissions this night, cannot ask the resident who evaluated this patient in the emergency department for further information because the shift has ended. The patient’s son left at the time of admission and is not available when the patient arrives on the medical ward.

The night float resident quickly examines the patient, enters admission orders, and signs the patient out to the intern and resident who will be caring for her during her hospitalization. The verbal handoff notes that the history was limited due to a language barrier. The initial problem list includes heart failure without a differential diagnosis, but notes that an elevated pro-BNP and chest radiograph confirm heart failure as the likely diagnosis.

Several hours after the night float resident has left, the resident presents this history to the attending physician, and together they decide to order her regular at-home medications, as well as deep vein thrombosis prophylaxis and echocardiography. In writing the orders, subcutaneous heparin once daily is erroneously entered instead of low-molecular-weight heparin daily, as this is the default in the medical record system. The tired resident fails to recognize this, and the pharmacist does not question it.

Over the next 2 days, the patient’s cough and shortness of breath persist.

After the attending physician dismisses their concerns, the residents do not bring up their idea again

On hospital day 3, two junior residents on the team (who finished their internship 2 weeks ago) review the attending radiologist’s interpretation of the chest radiograph. Unflagged, it confirms the resident’s interpretation but notes ill-defined, scattered, faint opacities. The residents believe that an interstitial pattern may be present and suggest that the patient may not have heart failure but rather a primary pulmonary disease. They bring this to the attention of their attending physician, who dismisses their concerns and comments that heart failure is a clinical diagnosis. The residents do not bring this idea up again to the attending physician.

That night, the float team is called by the nursing staff because of worsening oxygenation and cough. They add an intravenous corticosteroid, a broad-spectrum antibiotic, and an inhaled bronchodilator to the patient’s drug regimen.

How do cognitive errors predispose physicians to diagnostic errors?

When errors in diagnosis are reviewed retrospectively, cognitive or “thinking” errors are generally found, especially in nonprocedural or primary care specialties such as internal medicine, pediatrics, and emergency medicine.^16,17

A widely accepted theory on how humans make decisions was described by the psychologists Tversky and Kahneman in 1974¹⁸ and has been applied more recently to physicians’ diagnostic processes.¹⁹ Their dual process model theory states that persons with a requisite level of expertise use either the intuitive “system 1” process of thinking, based on pattern-recognition and heuristics, or the slower, more analytical “system 2” process.²⁰ Experts disagree as to whether in medicine these processes represent a binary either-or model or a continuum²¹ with relative contributions of each process determined by the physician and the task.

What are some common types of cognitive error?

Experts agree that many diagnostic errors in medicine stem from decisions arrived at by inappropriate system 1 thinking due to biases. These biases have been identified and described as they relate to medicine, most notably by Croskerry.²²

Several cognitive biases are illustrated in our clinical scenario:

The framing effect occurred when the emergency department resident listed the patient’s admitting diagnosis as heart failure during the clinical handoff of care.

Anchoring bias, as defined by Croskerry,²² is the tendency to lock onto salient features of the case too early in the diagnostic process and then to fail to adjust this initial diagnostic impression. This bias affected the admitting night float resident, primary intern, resident, and attending physician.

Diagnostic momentum, in turn, is a well-described phenomenon that clinical providers are especially vulnerable to in today’s environment of “copy-and-paste” medical records and numerous handovers of care as a consequence of residency duty-hour restrictions.²³

Availability bias refers to commonly seen diagnoses like heart failure or recently seen diagnoses, which are more “available” to the human memory. These diagnoses, which spring to mind quickly, often trick providers into thinking that because they are more easily recalled, they are also more common or more likely.

Confirmation bias. The initial working diagnosis of heart failure may have led the medical team to place greater emphasis on the elevated pro-BNP and the chest radiograph to support the initial impression while ignoring findings such as weight loss that do not support this impression.

Blind obedience. Although the residents recognized the possibility of a primary pulmonary disease, they did not investigate this further. And when the attending physician dismissed their suggestion, they thus deferred to the person in authority or with a reputation of expertise.

Overconfidence bias. Despite minimal improvement in the patient’s clinical status after effective diuresis and the suggestion of alternative diagnoses by the residents, the attending physician remained confident—perhaps overconfident—in the diagnosis of heart failure and would not consider alternatives. Overconfidence bias has been well described and occurs when a medical provider believes too strongly in his or her ability to be correct and therefore fails to consider alternative diagnoses.²⁴

Despite succumbing to overconfidence bias, the attending physician was able to overcome base-rate neglect, ie, failure to consider the prevalence of potential diagnoses in diagnostic reasoning.

Each of these biases, and others not mentioned, can lead to premature closure, which is the unfortunate root cause of many diagnostic errors and delays. We have illustrated several biases in our case scenario that led several physicians on the medical team to prematurely “close” on the diagnosis of heart failure (Table 1).

CASE CONTINUED: SURPRISES AND REASSESSMENT

On hospital day 4, the patient’s medication lists from her previous hospitalizations arrive, and the team is surprised to discover that she has been receiving infliximab for the past 3 to 4 months for her rheumatoid arthritis.

Additionally, an echocardiogram that was ordered on hospital day 1 but was lost in the cardiologist’s reading queue comes in and shows a normal ejection fraction with no evidence of elevated filling pressures.

Computed tomography of the chest reveals a reticular pattern with innumerable, tiny, 1- to 2-mm pulmonary nodules. The differential diagnosis is expanded to include hypersensitivity pneumonitis, lymphoma, fungal infection, and miliary tuberculosis.

How do faulty systems contribute to diagnostic error?

It is increasingly recognized that diagnostic errors can occur as a result of cognitive error, systems-based error, or quite commonly, both. Graber et al¹⁷ analyzed 100 cases of diagnostic error and determined that while cognitive errors did occur in most of them, nearly half the time both cognitive and systems-based errors contributed simultaneously.¹⁷ Observers have further delineated the importance of the systems context and how it affects our thinking.²⁵

In this case, the language barrier, lack of availability of family, and inability to promptly utilize interpreter services contributed to early problems in acquiring a detailed history and a complete medication list that included the immunosuppressant infliximab. Later, a systems error led to a delay in the interpretation of an echocardiogram. Each of these factors, if prevented, would have presumably resulted in expansion of the differential diagnosis and earlier arrival at the correct diagnosis.

CASE CONTINUED: THE PATIENT DIES OF TUBERCULOSIS

The patient is moved to a negative pressure room, and the pulmonary consultants recommend bronchoscopy. During the procedure, the patient suffers acute respiratory failure, is intubated, and is transferred to the medical intensive care unit, where a saddle pulmonary embolism is diagnosed by computed tomographic angiography.

One day later, the sputum culture from the bronchoscopy returns as positive for acid-fast bacilli. A four-drug regimen for tuberculosis is started. The patient continues to have a downward course and expires 2 weeks later. Autopsy reveals miliary tuberculosis.

What is the frequency of diagnostic error in medicine?

Diagnostic error is estimated to have a frequency of 10% to 20%.²⁴ Rates of diagnostic error are similar irrespective of method of determination, eg, from autopsy,³ standardized patients (ie, actors presenting with scripted scenarios),²⁶ or case reviews.²⁷ Patient surveys report patient-perceived harm from diagnostic error at a rate of 35% to 42%.^28,29 The landmark Harvard Medical Practice Study found that 17% of all adverse events were attributable to diagnostic error.³⁰

Diagnostic error is the most common type of medical error in nonprocedural medical fields.³¹ It causes a disproportionately large amount of morbidity and death.

Diagnostic error is the most common cause of malpractice claims in the United States. In inpatient and outpatient settings, for both medical and surgical patients, it accounted for 45.9% of all outpatient malpractice claims in 2009, making it the most common reason for medical malpractice litigation.³² A 2013 study indicated that diagnostic error is more common, more expensive, and two times more likely to result in death than any other category of error.³³

CASE CONTINUED: MORBIDITY AND MORTALITY CONFERENCE

The patient’s case is brought to a morbidity and mortality conference for discussion. The systems issues in the case—including medication reconciliation, availability of interpreters, and timing and process of echocardiogram readings—are all discussed, but clinical reasoning and cognitive errors made in the case are avoided.

Why are cognitive errors often neglected in discussions of medical error?

Historically, openly discussing error in medicine has been difficult. Over the past decade, however, and fueled by the landmark Institute of Medicine report To Err is Human,³⁴ the healthcare community has made substantial strides in identifying and talking about systems factors as a cause of preventable medical error.^34,35

While systems contributions to medical error are inherently “external” to physicians and other healthcare providers, the cognitive contributions to error are inherently “internal” and are often considered personal. This has led to diagnostic error being kept out of many patient safety conversations. Further, while the solutions to systems errors are often tangible, such as implementing a fall prevention program or changing the physical packaging of a medication to reduce a medication dispensing or administration error, solutions to cognitive errors are generally considered more challenging to address by organizations trying to improve patient safety.

How can hospitals and department leaders do better?

Healthcare organizations and leaders of clinical teams or departments can implement several strategies.³⁶

First, they can seek out and analyze the causes of diagnostic errors that are occurring locally in their institution and learn from their diagnostic errors, such as the one in our clinical scenario.

Trainees, physicians, and nurses should be comfortable questioning each other

Second, they can promote a culture of open communication and questioning around diagnosis. Trainees, physicians, and nurses should be comfortable questioning each other, including those higher up in the hierarchy, by saying, “I’m not sure” or “What else could this be?” to help reduce cognitive bias and expand the diagnostic possibilities.

Similarly, developing strategies to promote feedback on diagnosis among physicians will allow us all to learn from our diagnostic mistakes.

Use of the electronic medical record to assist in follow-up of pending diagnostic studies and patient return visits is yet another strategy.

Finally, healthcare organizations can adopt strategies to promote patient involvement in diagnosis, such as providing patients with copies of their test results and discharge summaries, encouraging the use of electronic patient communication portals, and empowering patients to ask questions related to their diagnosis. Prioritizing potential solutions to reduce diagnostic errors may be helpful in situations, depending on the context and environment, in which all proposed interventions may not be possible.

CASE CONTINUED: LEARNING FROM MISTAKES

The attending physician and resident in the case meet after the conference to review their clinical decision-making. Both are interested in learning from this case and improving their diagnostic skills in the future.

What specific steps can clinicians take to mitigate cognitive bias in daily practice?

In addition to continuing to expand one’s medical knowledge and gain more clinical experience, we can suggest several small steps to busy clinicians, taken individually or in combination with others that may improve diagnostic skills by reducing the potential for biased thinking in clinical practice.

From Croskerry P. Clinical cognition and diagnostic error: applications of a dual process model of reasoning. Adv Health Sci Educ 2009; 14:27–35. With kind permission from Springer Science and Business Media.

Think about your thinking. Our first recommendation would be to become more familiar with the dual process theory of clinical cognition (Figure 1).^37,38 This theoretical framework may be very helpful as a foundation from which to build better thinking skills. Physicians, especially residents, and students can be taught these concepts and their potential to contribute to diagnostic errors, and can use these skills to recognize those contributions in others’ diagnostic practices and even in their own.³⁹

Facilitating metacognition, or “thinking about one’s thinking,” may help clinicians catch themselves in thinking traps and provide the opportunity to reflect on biases retrospectively, as a double check or an opportunity to learn from a mistake.

Recognize your emotions. Gaining an understanding of the effect of one’s emotions on decision-making also can help clinicians free themselves of bias. As human beings, healthcare professionals are  susceptible to emotion, and the best approach to mitigate the emotional influences may be to consciously name them and adjust for them.⁴⁰

Because it is impractical to apply slow, analytical system 2 approaches to every case, skills that hone and develop more accurate, reliable system 1 thinking are crucial. Gaining broad exposure to increased numbers of cases may be the most reliable way to build an experiential repertoire of “illness scripts,” but there are ways to increase the experiential value of any case with a few techniques that have potential to promote better intuition.⁴¹

Embracing uncertainty in the early diagnostic process and envisioning the worst-case scenario in a case allows the consideration of additional diagnostic paths outside of the current working diagnosis, potentially priming the clinician to look for and recognize early warning signs that could argue against the initial diagnosis at a time when an adjustment could be made to prevent a bad outcome.

Practice progressive problem-solving,⁴² a technique in which the physician creates additional challenges to increase the cognitive burden of a “routine” case in an effort to train his or her mind and sharpen intuition. An example of this practice is contemplating a backup treatment plan in advance in the event of a poor response to or an adverse effect of treatment. Highly rated physicians and teachers perform this regularly.^43,44 Other ways to maximize the learning value of an individual case include seeking feedback on patient outcomes, especially when a patient has been discharged or transferred to another provider’s care, or when the physician goes off service.

Simulation, traditionally used for procedural training, has potential as well. Cognitive simulation, such as case reports or virtual patient modules, have potential to enhance clinical reasoning skills as well, though possibly at greater cost of time and expense.

Decreased reliance on memory is likely to improve diagnostic reasoning. Systems tools such as checklists⁴⁵ and health information technology⁴⁶ have potential to reduce diagnostic errors, not by taking thinking away from the clinician but by relieving the cognitive load enough to facilitate greater effort toward reasoning.

Slow down. Finally, and perhaps most important, recent models of clinical expertise have suggested that mastery comes from having a robust intuitive method, with a sense of the limitations of the intuitive approach, an ability to recognize the need to perform more analytical reasoning in select cases, and the willingness to do so. In short, it may well be that the hallmark of a master clinician is the propensity to slow down when necessary.⁴⁷

A ‘diagnostic time-out’ for safety might catch opportunities to recognize and mitigate biases and errors

If one considers diagnosis a cognitive procedure, perhaps a brief “diagnostic time-out” for safety might afford an opportunity to recognize and mitigate biases and errors. There are likely many potential scripts for a good diagnostic time-out, but to be functional it should be brief and simple to facilitate consistent use. We have recommended the following four questions to our residents as a starting point, any of which could signal the need to switch to a slower, analytic approach.

Four-step diagnostic time-out

• What else can it be?
• Is there anything about the case that does not fit?
• Is it possible that multiple processes are going on?
• Do I need to slow down?

These questions can serve as a double check for an intuitively formed initial working diagnosis, incorporating many of the principles discussed above, in a way that would hopefully avoid undue burden on a busy clinician. These techniques, it must be acknowledged, have not yet been directly tied to reductions in diagnostic errors. However, diagnostic errors, as discussed, are very difficult to identify and study, and these techniques will serve mainly to improve habits that are likely to show benefits over much longer time periods than most studies can measure.

SAN ANTONIO – Patients who have low-risk, human papillomavirus (HPV)–associated oropharyngeal cancers may be effectively and safely treated with a reduced intensity chemoradiotherapy regimen, according to research presented at the annual meeting of the American Society for Radiation Oncology.

In the prospective, multi-institutional, phase II trial, complete pathologic responses (pCR) were seen in 86% of the 43 patients treated. The six cases that did not show a pCR were limited to microscopic areas of residual cancer.

ASTRO/Adam Donohue

The study provides strong preliminary evidence that reduced intensity chemoradiotherapy may be as effective as standard-dose chemoradiotherapy, Dr. Bhishamjit Chera of the University of North Carolina at Chapel Hill said at a press briefing. While it is too early to use outside of a clinical trial at present, he said, there is the potential for less intensive treatment to be given, and it could be the standard practice in years to come.

“At most institutions, the standard treatment for oropharynx cancer is definite chemoradiation,” Dr. Chera explained. This typically involves delivery of 70 Gy of radiation, given in 2-Gy fractions over 7 weeks for a total 35 days of treatment, and administration of three doses of cisplatin 100 mg/m² concurrently.

“This treatment provides the best chances of sparing the tonsil, the throat, and the tongue, basically preserving organ function,” he added. Surgery is not usually performed unless there are signs on imaging that the cancer has not completely resolved 12 weeks after treatment.

“We know that many patients are cured with oropharyngeal carcinoma, but many patients live with significant long-term side effects such as dry mouth and difficulty swallowing,” Dr. Chera observed. Thus the aim of the present trial was to see if reducing the intensity of the chemoradiotherapy might avoid some of the side effects seen.

The deintensified regimen used in the study consisted of a 10-Gy reduction in the total dose of radiation delivered to 60 Gy, which was given in 2-Gy fractions once daily over a period of 6 weeks. The dose of cisplatin also was reduced by approximately 40% to 30 mg/m² given in 6 weekly doses

Patients were eligible for inclusion if they had stage 0-3 squamous cell carcinoma of the oropharynx, with limited nodal (N0-N2c) and no metastatic involvement. Patients had to have a minimal smoking history and be HPV or p16 positive.

After the chemoradiation, all patients underwent a planned biopsy and limited neck dissection to remove any lymph nodes that had cancer in them prior to treatment. Thus the primary endpoint was the pCR rather a radiographically measured tumor response rate, Dr. Chera observed.

Considering just the primary site of the cancer (the base of tongue and tonsil), there were 41 patients who could be evaluated and all but one of these (98%) achieved a pCR. Looking at patients with neck involvement at baseline (n = 39), 84% achieved a pCR.

“All of these 43 patients are alive with no evidence of cancer recurrence with a follow-up of 21 months,” Dr. Chera reported.

Throughout the study, patient-reported outcomes were captured using the National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) and the European Organization for Cancer Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ).

While patients did report an increase in adverse effects 6-8 weeks after the chemoradiation, the intensity of these side effects decreased to baseline levels over time. Not surprisingly, the two most common symptoms were dry mouth and problems with swallowing, with 75% and 55% of patients, respectively, experiencing severe or very severe xerostomia and dysphagia. Other grade 3-4 adverse events included mucositis in 45%, pain in 48%, nausea in 52%, and vomiting in 34%.

Results of the quality of life analyses show that patients’ quality of life is returning to baseline levels after 1 year.

“There is a lot of interest in reducing the intensity of treatment in these patients,” Dr. Chera said, adding that patients are likely being overtreated at present. In the current clinical environment, patients are very savvy, he said, so performing a large randomized phase III trial may not be possible if patients learn that deintensified therapy may be an option. So the results of larger and longer phase II trials may be the best evidence that will be obtained.

The NRG Oncology group is going to evaluate the same deintensified chemotherapy regimen in another, larger phase II trial, the NRG-HN002 trial, Dr. Chera said. This trial aims to accrue almost 300 patients and will compare the University of North Carolina regimen versus radiation alone, which will be given at a total dose of 50 Gy 5 days a week for 5 weeks.

And, as for his group’s further research plans, Dr. Chera noted in an interview that further follow-up would be required to determine if the regimen used was efficacious and safe. A second phase II trial with the same deintensified regimen in which surgery or biopsies were not mandated is about to close soon, and there is a third study that will look at using genetic information to determine if it is safe to deintensifty patients’ treatment.

Dr. Chera had no conflicts of interest to disclose.

tor@frontlinemedcom.com

SAN ANTONIO – Patients who have low-risk, human papillomavirus (HPV)–associated oropharyngeal cancers may be effectively and safely treated with a reduced intensity chemoradiotherapy regimen, according to research presented at the annual meeting of the American Society for Radiation Oncology.

In the prospective, multi-institutional, phase II trial, complete pathologic responses (pCR) were seen in 86% of the 43 patients treated. The six cases that did not show a pCR were limited to microscopic areas of residual cancer.

ASTRO/Adam Donohue

The study provides strong preliminary evidence that reduced intensity chemoradiotherapy may be as effective as standard-dose chemoradiotherapy, Dr. Bhishamjit Chera of the University of North Carolina at Chapel Hill said at a press briefing. While it is too early to use outside of a clinical trial at present, he said, there is the potential for less intensive treatment to be given, and it could be the standard practice in years to come.

“At most institutions, the standard treatment for oropharynx cancer is definite chemoradiation,” Dr. Chera explained. This typically involves delivery of 70 Gy of radiation, given in 2-Gy fractions over 7 weeks for a total 35 days of treatment, and administration of three doses of cisplatin 100 mg/m² concurrently.

“This treatment provides the best chances of sparing the tonsil, the throat, and the tongue, basically preserving organ function,” he added. Surgery is not usually performed unless there are signs on imaging that the cancer has not completely resolved 12 weeks after treatment.

“We know that many patients are cured with oropharyngeal carcinoma, but many patients live with significant long-term side effects such as dry mouth and difficulty swallowing,” Dr. Chera observed. Thus the aim of the present trial was to see if reducing the intensity of the chemoradiotherapy might avoid some of the side effects seen.

The deintensified regimen used in the study consisted of a 10-Gy reduction in the total dose of radiation delivered to 60 Gy, which was given in 2-Gy fractions once daily over a period of 6 weeks. The dose of cisplatin also was reduced by approximately 40% to 30 mg/m² given in 6 weekly doses

Patients were eligible for inclusion if they had stage 0-3 squamous cell carcinoma of the oropharynx, with limited nodal (N0-N2c) and no metastatic involvement. Patients had to have a minimal smoking history and be HPV or p16 positive.

After the chemoradiation, all patients underwent a planned biopsy and limited neck dissection to remove any lymph nodes that had cancer in them prior to treatment. Thus the primary endpoint was the pCR rather a radiographically measured tumor response rate, Dr. Chera observed.

Considering just the primary site of the cancer (the base of tongue and tonsil), there were 41 patients who could be evaluated and all but one of these (98%) achieved a pCR. Looking at patients with neck involvement at baseline (n = 39), 84% achieved a pCR.

“All of these 43 patients are alive with no evidence of cancer recurrence with a follow-up of 21 months,” Dr. Chera reported.

Throughout the study, patient-reported outcomes were captured using the National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) and the European Organization for Cancer Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ).

While patients did report an increase in adverse effects 6-8 weeks after the chemoradiation, the intensity of these side effects decreased to baseline levels over time. Not surprisingly, the two most common symptoms were dry mouth and problems with swallowing, with 75% and 55% of patients, respectively, experiencing severe or very severe xerostomia and dysphagia. Other grade 3-4 adverse events included mucositis in 45%, pain in 48%, nausea in 52%, and vomiting in 34%.

Results of the quality of life analyses show that patients’ quality of life is returning to baseline levels after 1 year.

“There is a lot of interest in reducing the intensity of treatment in these patients,” Dr. Chera said, adding that patients are likely being overtreated at present. In the current clinical environment, patients are very savvy, he said, so performing a large randomized phase III trial may not be possible if patients learn that deintensified therapy may be an option. So the results of larger and longer phase II trials may be the best evidence that will be obtained.

The NRG Oncology group is going to evaluate the same deintensified chemotherapy regimen in another, larger phase II trial, the NRG-HN002 trial, Dr. Chera said. This trial aims to accrue almost 300 patients and will compare the University of North Carolina regimen versus radiation alone, which will be given at a total dose of 50 Gy 5 days a week for 5 weeks.

And, as for his group’s further research plans, Dr. Chera noted in an interview that further follow-up would be required to determine if the regimen used was efficacious and safe. A second phase II trial with the same deintensified regimen in which surgery or biopsies were not mandated is about to close soon, and there is a third study that will look at using genetic information to determine if it is safe to deintensifty patients’ treatment.

Dr. Chera had no conflicts of interest to disclose.

tor@frontlinemedcom.com

SAN ANTONIO – Patients who have low-risk, human papillomavirus (HPV)–associated oropharyngeal cancers may be effectively and safely treated with a reduced intensity chemoradiotherapy regimen, according to research presented at the annual meeting of the American Society for Radiation Oncology.

In the prospective, multi-institutional, phase II trial, complete pathologic responses (pCR) were seen in 86% of the 43 patients treated. The six cases that did not show a pCR were limited to microscopic areas of residual cancer.

ASTRO/Adam Donohue

The study provides strong preliminary evidence that reduced intensity chemoradiotherapy may be as effective as standard-dose chemoradiotherapy, Dr. Bhishamjit Chera of the University of North Carolina at Chapel Hill said at a press briefing. While it is too early to use outside of a clinical trial at present, he said, there is the potential for less intensive treatment to be given, and it could be the standard practice in years to come.

“At most institutions, the standard treatment for oropharynx cancer is definite chemoradiation,” Dr. Chera explained. This typically involves delivery of 70 Gy of radiation, given in 2-Gy fractions over 7 weeks for a total 35 days of treatment, and administration of three doses of cisplatin 100 mg/m² concurrently.

“This treatment provides the best chances of sparing the tonsil, the throat, and the tongue, basically preserving organ function,” he added. Surgery is not usually performed unless there are signs on imaging that the cancer has not completely resolved 12 weeks after treatment.

“We know that many patients are cured with oropharyngeal carcinoma, but many patients live with significant long-term side effects such as dry mouth and difficulty swallowing,” Dr. Chera observed. Thus the aim of the present trial was to see if reducing the intensity of the chemoradiotherapy might avoid some of the side effects seen.

The deintensified regimen used in the study consisted of a 10-Gy reduction in the total dose of radiation delivered to 60 Gy, which was given in 2-Gy fractions once daily over a period of 6 weeks. The dose of cisplatin also was reduced by approximately 40% to 30 mg/m² given in 6 weekly doses

Patients were eligible for inclusion if they had stage 0-3 squamous cell carcinoma of the oropharynx, with limited nodal (N0-N2c) and no metastatic involvement. Patients had to have a minimal smoking history and be HPV or p16 positive.

After the chemoradiation, all patients underwent a planned biopsy and limited neck dissection to remove any lymph nodes that had cancer in them prior to treatment. Thus the primary endpoint was the pCR rather a radiographically measured tumor response rate, Dr. Chera observed.

Considering just the primary site of the cancer (the base of tongue and tonsil), there were 41 patients who could be evaluated and all but one of these (98%) achieved a pCR. Looking at patients with neck involvement at baseline (n = 39), 84% achieved a pCR.

“All of these 43 patients are alive with no evidence of cancer recurrence with a follow-up of 21 months,” Dr. Chera reported.

Throughout the study, patient-reported outcomes were captured using the National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) and the European Organization for Cancer Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ).

While patients did report an increase in adverse effects 6-8 weeks after the chemoradiation, the intensity of these side effects decreased to baseline levels over time. Not surprisingly, the two most common symptoms were dry mouth and problems with swallowing, with 75% and 55% of patients, respectively, experiencing severe or very severe xerostomia and dysphagia. Other grade 3-4 adverse events included mucositis in 45%, pain in 48%, nausea in 52%, and vomiting in 34%.

Results of the quality of life analyses show that patients’ quality of life is returning to baseline levels after 1 year.

“There is a lot of interest in reducing the intensity of treatment in these patients,” Dr. Chera said, adding that patients are likely being overtreated at present. In the current clinical environment, patients are very savvy, he said, so performing a large randomized phase III trial may not be possible if patients learn that deintensified therapy may be an option. So the results of larger and longer phase II trials may be the best evidence that will be obtained.

The NRG Oncology group is going to evaluate the same deintensified chemotherapy regimen in another, larger phase II trial, the NRG-HN002 trial, Dr. Chera said. This trial aims to accrue almost 300 patients and will compare the University of North Carolina regimen versus radiation alone, which will be given at a total dose of 50 Gy 5 days a week for 5 weeks.

And, as for his group’s further research plans, Dr. Chera noted in an interview that further follow-up would be required to determine if the regimen used was efficacious and safe. A second phase II trial with the same deintensified regimen in which surgery or biopsies were not mandated is about to close soon, and there is a third study that will look at using genetic information to determine if it is safe to deintensifty patients’ treatment.

Dr. Chera had no conflicts of interest to disclose.

tor@frontlinemedcom.com

Red blood cells

ANAHEIM, CA—Interim results of a large study suggest a blood donor’s genetic background and frequency of donation influence

red blood cell (RBC) storage and stress hemolysis.

Investigators found that donor ethnicity and gender both affected hemolysis, but the effects sometimes differed between storage and stress hemolysis.

Similarly, RBCs from frequent donors were more susceptible to storage and osmotic hemolysis but less susceptible to oxidative hemolysis.

Tamir Kanias, PhD, of the University of Pittsburgh in Pennsylvania, presented these findings at the 2015 AABB Annual Meeting (abstract S73-040A).

“We now know that some donor red cells store very well, and, even after 42 days of storage, there is hardly any hemolysis,” Dr Kanias noted. “[But for] some donors, their red cells are starting to degrade maybe 5 or 6 days after collection.”

With that in mind, Dr Kanias and his colleagues set out to define the genetic and metabolic basis for donor-specific differences in hemolysis in stored RBCs.

They analyzed RBCs collected at 4 centers as part of the REDS-III study. The team took 15 mL of RBCs from fresh units donated for transfusion and stored the cells in transfer bags to measure hemolysis. The transfer bags are miniature versions of the bags used to store RBCs for transfusion.

Dr Kanias presented interim findings in samples from more than 8000 donors. He and his colleagues looked at donor ethnicity, gender, and age. The team also assessed whether subjects were “high-intensity” donors, which was defined as donating RBCs 10 or more times in the previous 24 months without a low-hemoglobin deferral.

The donors’ samples were stored for 39 to 42 days before the investigators assessed hemolysis. They measured end-of-storage hemolysis in unwashed red cells, then washed the RBCs and assessed osmotic hemolysis (Pink test) and oxidative hemolysis (AAPH).

Ethnicity and intensity

Tests showed that RBCs from African American and high-intensity donors (more than 90% of whom were Caucasian) were more susceptible to storage hemolysis than RBCs from the other donor groups analyzed.

RBCs from Caucasian donors and high-intensity donors were susceptible to osmotic hemolysis, while RBCs from African American and Asian donors were more resistant.

“We hypothesize that this [resistance] may be related to some of these donors carrying traits for sickle cell disease or thalassemia,” Dr Kanias said. “Both diseases are known to render red cells more resistant to osmotic hemolysis, but of course, it could be [explained by] new mutations that we don’t know of.”

RBCs from Hispanic donors and African American donors were more susceptible to oxidative hemolysis, but the opposite was true of RBCs from high-intensity donors.

“What was really interesting is that the high-intensity donors that had higher end-of-storage hemolysis and higher susceptibility to osmotic hemolysis actually became more resistant to oxidative hemolysis,” Dr Kanias said.

“It is possible that the lower levels of iron in the red cells of these donors actually protects from oxidative hemolysis. Iron is redox-active, and a lot of the AAPH-induced hemolysis is mediated by iron interactions.”

Group comparisons

Looking at the data another way, the investigators compared samples from Caucasians to samples from the other ethnic groups and the high-intensity donors.

RBCs from African American donors had significantly higher storage hemolysis (P=0.0078), lower osmotic hemolysis (P<0.0001), and higher oxidative hemolysis (P=0.0008) than RBCs from Caucasians.

RBCs from Asians had significantly lower osmotic hemolysis (P<0.0001) than Caucasian RBCs, but there was no significant difference in storage hemolysis (P=0.69) or oxidative hemolysis (P=0.41) between the 2 groups.

RBCs from Hispanic donors were significantly more susceptible to oxidative hemolysis (P<0.0001) than Caucasian RBCs, but there was no significant difference between the groups with regard to storage hemolysis (P=0.89) or osmotic hemolysis (P=0.10).

RBCs from high-intensity donors had significantly higher storage hemolysis (P<0.0001) and lower oxidative hemolysis (P<0.0001) than Caucasian RBCs. There was no significant difference in osmotic hemolysis (P=0.84)

Gender and age

As in other studies, Dr Kanias and his colleagues found that RBCs from females hemolyzed significantly less than RBCs from males. This was true for storage hemolysis, osmotic hemolysis, and oxidative hemolysis (P<0.0001 for all).

“Just to note, the gender effect was more dramatic in storage and osmotic rather than oxidative, which suggests that the gender effect is more on the membrane or membrane integrity rather than antioxidant capacity,” Dr Kanias said.

He and his colleagues then looked at donor age and observed the gender effect at every age analyzed (18 to 65+). He noted that hemolysis fluctuated throughout the age groups, so the investigators couldn’t draw any concrete conclusions about hemolysis and donor age.

“One interesting thing to note is that, in all the assays, in young males—like around 20—there’s an increase in hemolysis where there’s a decrease in females,” Dr Kanias said. “This may be related to the effect of sex hormones.”

Genetic modifiers

The investigators also assessed how the 3 hemolytic assays relate to each other and found very weak correlations between them. Pearson correlations were 0.12 between storage and osmotic hemolysis, 0.0041 between storage and oxidative hemolysis, and 0.058 between osmotic and oxidative hemolysis.

“This is kind of cool because it may mean that there is a different genetic modifier affecting each of these phenomena,” Dr Kanias said.

He and his colleagues are now working to identify genetic and metabolic modifiers of hemolysis.

Red blood cells

ANAHEIM, CA—Interim results of a large study suggest a blood donor’s genetic background and frequency of donation influence

red blood cell (RBC) storage and stress hemolysis.

Investigators found that donor ethnicity and gender both affected hemolysis, but the effects sometimes differed between storage and stress hemolysis.

Similarly, RBCs from frequent donors were more susceptible to storage and osmotic hemolysis but less susceptible to oxidative hemolysis.

Tamir Kanias, PhD, of the University of Pittsburgh in Pennsylvania, presented these findings at the 2015 AABB Annual Meeting (abstract S73-040A).

“We now know that some donor red cells store very well, and, even after 42 days of storage, there is hardly any hemolysis,” Dr Kanias noted. “[But for] some donors, their red cells are starting to degrade maybe 5 or 6 days after collection.”

With that in mind, Dr Kanias and his colleagues set out to define the genetic and metabolic basis for donor-specific differences in hemolysis in stored RBCs.

They analyzed RBCs collected at 4 centers as part of the REDS-III study. The team took 15 mL of RBCs from fresh units donated for transfusion and stored the cells in transfer bags to measure hemolysis. The transfer bags are miniature versions of the bags used to store RBCs for transfusion.

Dr Kanias presented interim findings in samples from more than 8000 donors. He and his colleagues looked at donor ethnicity, gender, and age. The team also assessed whether subjects were “high-intensity” donors, which was defined as donating RBCs 10 or more times in the previous 24 months without a low-hemoglobin deferral.

The donors’ samples were stored for 39 to 42 days before the investigators assessed hemolysis. They measured end-of-storage hemolysis in unwashed red cells, then washed the RBCs and assessed osmotic hemolysis (Pink test) and oxidative hemolysis (AAPH).

Ethnicity and intensity

Tests showed that RBCs from African American and high-intensity donors (more than 90% of whom were Caucasian) were more susceptible to storage hemolysis than RBCs from the other donor groups analyzed.

RBCs from Caucasian donors and high-intensity donors were susceptible to osmotic hemolysis, while RBCs from African American and Asian donors were more resistant.

“We hypothesize that this [resistance] may be related to some of these donors carrying traits for sickle cell disease or thalassemia,” Dr Kanias said. “Both diseases are known to render red cells more resistant to osmotic hemolysis, but of course, it could be [explained by] new mutations that we don’t know of.”

RBCs from Hispanic donors and African American donors were more susceptible to oxidative hemolysis, but the opposite was true of RBCs from high-intensity donors.

“What was really interesting is that the high-intensity donors that had higher end-of-storage hemolysis and higher susceptibility to osmotic hemolysis actually became more resistant to oxidative hemolysis,” Dr Kanias said.

“It is possible that the lower levels of iron in the red cells of these donors actually protects from oxidative hemolysis. Iron is redox-active, and a lot of the AAPH-induced hemolysis is mediated by iron interactions.”

Group comparisons

Looking at the data another way, the investigators compared samples from Caucasians to samples from the other ethnic groups and the high-intensity donors.

RBCs from African American donors had significantly higher storage hemolysis (P=0.0078), lower osmotic hemolysis (P<0.0001), and higher oxidative hemolysis (P=0.0008) than RBCs from Caucasians.

RBCs from Asians had significantly lower osmotic hemolysis (P<0.0001) than Caucasian RBCs, but there was no significant difference in storage hemolysis (P=0.69) or oxidative hemolysis (P=0.41) between the 2 groups.

RBCs from Hispanic donors were significantly more susceptible to oxidative hemolysis (P<0.0001) than Caucasian RBCs, but there was no significant difference between the groups with regard to storage hemolysis (P=0.89) or osmotic hemolysis (P=0.10).

RBCs from high-intensity donors had significantly higher storage hemolysis (P<0.0001) and lower oxidative hemolysis (P<0.0001) than Caucasian RBCs. There was no significant difference in osmotic hemolysis (P=0.84)

Gender and age

As in other studies, Dr Kanias and his colleagues found that RBCs from females hemolyzed significantly less than RBCs from males. This was true for storage hemolysis, osmotic hemolysis, and oxidative hemolysis (P<0.0001 for all).

“Just to note, the gender effect was more dramatic in storage and osmotic rather than oxidative, which suggests that the gender effect is more on the membrane or membrane integrity rather than antioxidant capacity,” Dr Kanias said.

He and his colleagues then looked at donor age and observed the gender effect at every age analyzed (18 to 65+). He noted that hemolysis fluctuated throughout the age groups, so the investigators couldn’t draw any concrete conclusions about hemolysis and donor age.

“One interesting thing to note is that, in all the assays, in young males—like around 20—there’s an increase in hemolysis where there’s a decrease in females,” Dr Kanias said. “This may be related to the effect of sex hormones.”

Genetic modifiers

The investigators also assessed how the 3 hemolytic assays relate to each other and found very weak correlations between them. Pearson correlations were 0.12 between storage and osmotic hemolysis, 0.0041 between storage and oxidative hemolysis, and 0.058 between osmotic and oxidative hemolysis.

“This is kind of cool because it may mean that there is a different genetic modifier affecting each of these phenomena,” Dr Kanias said.

He and his colleagues are now working to identify genetic and metabolic modifiers of hemolysis.

Red blood cells

ANAHEIM, CA—Interim results of a large study suggest a blood donor’s genetic background and frequency of donation influence

red blood cell (RBC) storage and stress hemolysis.

Investigators found that donor ethnicity and gender both affected hemolysis, but the effects sometimes differed between storage and stress hemolysis.

Similarly, RBCs from frequent donors were more susceptible to storage and osmotic hemolysis but less susceptible to oxidative hemolysis.

Tamir Kanias, PhD, of the University of Pittsburgh in Pennsylvania, presented these findings at the 2015 AABB Annual Meeting (abstract S73-040A).

“We now know that some donor red cells store very well, and, even after 42 days of storage, there is hardly any hemolysis,” Dr Kanias noted. “[But for] some donors, their red cells are starting to degrade maybe 5 or 6 days after collection.”

With that in mind, Dr Kanias and his colleagues set out to define the genetic and metabolic basis for donor-specific differences in hemolysis in stored RBCs.

They analyzed RBCs collected at 4 centers as part of the REDS-III study. The team took 15 mL of RBCs from fresh units donated for transfusion and stored the cells in transfer bags to measure hemolysis. The transfer bags are miniature versions of the bags used to store RBCs for transfusion.

Dr Kanias presented interim findings in samples from more than 8000 donors. He and his colleagues looked at donor ethnicity, gender, and age. The team also assessed whether subjects were “high-intensity” donors, which was defined as donating RBCs 10 or more times in the previous 24 months without a low-hemoglobin deferral.

The donors’ samples were stored for 39 to 42 days before the investigators assessed hemolysis. They measured end-of-storage hemolysis in unwashed red cells, then washed the RBCs and assessed osmotic hemolysis (Pink test) and oxidative hemolysis (AAPH).

Ethnicity and intensity

Tests showed that RBCs from African American and high-intensity donors (more than 90% of whom were Caucasian) were more susceptible to storage hemolysis than RBCs from the other donor groups analyzed.

RBCs from Caucasian donors and high-intensity donors were susceptible to osmotic hemolysis, while RBCs from African American and Asian donors were more resistant.

“We hypothesize that this [resistance] may be related to some of these donors carrying traits for sickle cell disease or thalassemia,” Dr Kanias said. “Both diseases are known to render red cells more resistant to osmotic hemolysis, but of course, it could be [explained by] new mutations that we don’t know of.”

RBCs from Hispanic donors and African American donors were more susceptible to oxidative hemolysis, but the opposite was true of RBCs from high-intensity donors.

“What was really interesting is that the high-intensity donors that had higher end-of-storage hemolysis and higher susceptibility to osmotic hemolysis actually became more resistant to oxidative hemolysis,” Dr Kanias said.

“It is possible that the lower levels of iron in the red cells of these donors actually protects from oxidative hemolysis. Iron is redox-active, and a lot of the AAPH-induced hemolysis is mediated by iron interactions.”

Group comparisons

Looking at the data another way, the investigators compared samples from Caucasians to samples from the other ethnic groups and the high-intensity donors.

RBCs from African American donors had significantly higher storage hemolysis (P=0.0078), lower osmotic hemolysis (P<0.0001), and higher oxidative hemolysis (P=0.0008) than RBCs from Caucasians.

RBCs from Asians had significantly lower osmotic hemolysis (P<0.0001) than Caucasian RBCs, but there was no significant difference in storage hemolysis (P=0.69) or oxidative hemolysis (P=0.41) between the 2 groups.

RBCs from Hispanic donors were significantly more susceptible to oxidative hemolysis (P<0.0001) than Caucasian RBCs, but there was no significant difference between the groups with regard to storage hemolysis (P=0.89) or osmotic hemolysis (P=0.10).

RBCs from high-intensity donors had significantly higher storage hemolysis (P<0.0001) and lower oxidative hemolysis (P<0.0001) than Caucasian RBCs. There was no significant difference in osmotic hemolysis (P=0.84)

Gender and age

As in other studies, Dr Kanias and his colleagues found that RBCs from females hemolyzed significantly less than RBCs from males. This was true for storage hemolysis, osmotic hemolysis, and oxidative hemolysis (P<0.0001 for all).

“Just to note, the gender effect was more dramatic in storage and osmotic rather than oxidative, which suggests that the gender effect is more on the membrane or membrane integrity rather than antioxidant capacity,” Dr Kanias said.

He and his colleagues then looked at donor age and observed the gender effect at every age analyzed (18 to 65+). He noted that hemolysis fluctuated throughout the age groups, so the investigators couldn’t draw any concrete conclusions about hemolysis and donor age.

“One interesting thing to note is that, in all the assays, in young males—like around 20—there’s an increase in hemolysis where there’s a decrease in females,” Dr Kanias said. “This may be related to the effect of sex hormones.”

Genetic modifiers

The investigators also assessed how the 3 hemolytic assays relate to each other and found very weak correlations between them. Pearson correlations were 0.12 between storage and osmotic hemolysis, 0.0041 between storage and oxidative hemolysis, and 0.058 between osmotic and oxidative hemolysis.

“This is kind of cool because it may mean that there is a different genetic modifier affecting each of these phenomena,” Dr Kanias said.

He and his colleagues are now working to identify genetic and metabolic modifiers of hemolysis.

Interstitial cystitis (IC) is a debilitating disease that presents with a constellation of symptoms, including pain, urinary urgency, frequency, nocturia, and small voided volumes in the absence of other identifiable etiologies.¹ The overall prevalence of IC among US women is between 2.7% and 6.5%—affecting approximately 3.3 to 7.9 million women²—and it results in substantial costs^1,3 and impairments in health-related quality of life.⁴ Unfortunately, there is a lack of consensus on the pathophysiology and etiology of this prevalent and costly disorder. Thus, therapies are often empiric, with limited evidence and variable levels of improvement.⁵

There has been no clear evidence that bladder inflammation (cystitis) is involved in the etiology or pathophysiology of the condition. As a result, there has been a movement to rename it “bladder pain syndrome.” Current literature refers to the spectrum of symptoms as interstitial cystitis/bladder pain syndrome (IC/BPS).

Currently, the American Urological Association (AUA) defines IC/BPS as an unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder,
 associated with lower urinary tract symptoms of more than 6 weeks’ duration, in the absence of infection or other identifiable causes.⁶ This is still a broad, clinical diagnosis that has significant overlap with other pain syndromes but allows for treatment to begin after a relatively short symptomatic period.⁷ Because gynecologists are frequently the main care providers for women, understanding the diagnosis and treatment options for IC/BPS is important to avoid delayed treatment in a difficult to diagnose population.

Recently, the AUA published an amendment to their 2011 management guidelines to provide direction to clinicians and patients regarding how to recognize IC/BPS, conduct valid diagnostic testing, and approach treatment with the goals of maximizing symptom control and patient quality of life.⁷

In this article, we review the AUA diagnostic and treatment algorithms and the results of recently published randomized trials comparing the efficacy of various treatment modalities for IC/BPS, including pentosoan polysulfate sodium (PPS; Elmiron, Janssen Pharmaceuticals, Titusville, New Jersey) and botulinum toxin (Botox, Allergan, Irvine, California) with hydrodistension.

Evaluation and treatment algorithms for IC/BPS: AUA guidelines

Hanno PM, Erickson D, Moldwin R, Faraday MM; American Urological Association. Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment. J Urol. 2015;193(5):1545−1553.

The diagnosis of IC/BPS can be challenging due to a wide spectrum of symptoms, physical examination findings, and clinical test responses. The AUA developed its diagnostic and treatment guidelines mostly based on expert opinion, but they do provide a framework to help clinicians determine whether or not treatment for IC/BPS is warranted. The primary principles for evaluation are presented in FIGURE 1.

 

7,8

It is important to establish baseline voiding symptoms and pain levels with objective, validated instruments, including a voiding diary (FIGURE 2)⁹ and such patient questionnaires as the O’Leary Sant Interstitial Cystitis Index (ICSI; FIGURE 3).¹⁰ Characteristic IC/BPS voiding frequency is 10 or more times per day (to relieve pain, not to relieve a fear of wetting, which would be expected in a patient with overactive bladder).⁸ The ICSI questionnaire
should be used primarily to establish baseline symptoms, not as a diagnostic tool. A score higher than 8 has been used as inclusion criteria for therapeutic trials, however.¹¹

 

FIGURE 2 Voiding diary9

FIGURE 3 O’Leary Sant Interstitial Cystitis Index10

It is unnecessary to primarily perform cystoscopy or urodynamics, as there are no agreed-upon diagnostic criteria for these modalities for IC/BPS. They may be considered, however, if the patient does not respond to first- and second-line therapies. Additionally, potassium sensitivity testing is painful and, in view of the paucity of benefits, the risk/benefit ratio is too high to recommend for clinical care.

Treatment: Conservative first
The treatment for IC/BPS should start with more conservative therapy (including behavioral management and physical therapy). If symptom control is inadequate, other modalities should be employed. Behavioral modifications should include:

 

• local heat/cold over the bladder and perineum
• avoidance of foods and fluids that are known to be common irritants (such as coffee and citrus)
• trial of elimination diet
• bladder training with urge suppression techniques.

As noted in FIGURE 1, first make sure that patients do not have a urinary tract infection. If culture results are negative and other criteria fit, consider the diagnosis of IC/BPS and offer therapies as outlined in the ­treat‑
ment algorithm (FIGURE 4).⁷ Repeated 
treatment for negative results of urine cultures in patients with frequency, urgency, and bladder pain can lead to unnecessary antibiotics and delayed treatment of IC/BPS.

 

7

Treatments in FIGURE 4 are ordered from most to least conservative, and initial treatment depends on symptom severity, 
clinician judgment, and patient preference. If at any point in the patient’s care the diagnosis is questioned or treatments have been ineffective, referral to a specialist, including urogynecology or urology, may be appropriate.

Managing pain
Pain management is an important component at all levels of therapy, and pharmacologic pain management principles for 
IC/BPS should be similar to those for management of other chronic pain states. Options primarily include nonsteroidal anti-
inflammatory drugs (NSAIDs) and urinary analgesics (pyridium). The use of narcotics presents the risks of tolerance and dependence. If their use is necessary, all narcotic prescriptions must come from a single source and should be used as a component of multimodality therapy to minimize narcotic use.

Interstitial cystitis (IC) is a debilitating disease that presents with a constellation of symptoms, including pain, urinary urgency, frequency, nocturia, and small voided volumes in the absence of other identifiable etiologies.¹ The overall prevalence of IC among US women is between 2.7% and 6.5%—affecting approximately 3.3 to 7.9 million women²—and it results in substantial costs^1,3 and impairments in health-related quality of life.⁴ Unfortunately, there is a lack of consensus on the pathophysiology and etiology of this prevalent and costly disorder. Thus, therapies are often empiric, with limited evidence and variable levels of improvement.⁵

There has been no clear evidence that bladder inflammation (cystitis) is involved in the etiology or pathophysiology of the condition. As a result, there has been a movement to rename it “bladder pain syndrome.” Current literature refers to the spectrum of symptoms as interstitial cystitis/bladder pain syndrome (IC/BPS).

Currently, the American Urological Association (AUA) defines IC/BPS as an unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder,
 associated with lower urinary tract symptoms of more than 6 weeks’ duration, in the absence of infection or other identifiable causes.⁶ This is still a broad, clinical diagnosis that has significant overlap with other pain syndromes but allows for treatment to begin after a relatively short symptomatic period.⁷ Because gynecologists are frequently the main care providers for women, understanding the diagnosis and treatment options for IC/BPS is important to avoid delayed treatment in a difficult to diagnose population.

Recently, the AUA published an amendment to their 2011 management guidelines to provide direction to clinicians and patients regarding how to recognize IC/BPS, conduct valid diagnostic testing, and approach treatment with the goals of maximizing symptom control and patient quality of life.⁷

In this article, we review the AUA diagnostic and treatment algorithms and the results of recently published randomized trials comparing the efficacy of various treatment modalities for IC/BPS, including pentosoan polysulfate sodium (PPS; Elmiron, Janssen Pharmaceuticals, Titusville, New Jersey) and botulinum toxin (Botox, Allergan, Irvine, California) with hydrodistension.

Evaluation and treatment algorithms for IC/BPS: AUA guidelines

Hanno PM, Erickson D, Moldwin R, Faraday MM; American Urological Association. Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment. J Urol. 2015;193(5):1545−1553.

The diagnosis of IC/BPS can be challenging due to a wide spectrum of symptoms, physical examination findings, and clinical test responses. The AUA developed its diagnostic and treatment guidelines mostly based on expert opinion, but they do provide a framework to help clinicians determine whether or not treatment for IC/BPS is warranted. The primary principles for evaluation are presented in FIGURE 1.

 

7,8

It is important to establish baseline voiding symptoms and pain levels with objective, validated instruments, including a voiding diary (FIGURE 2)⁹ and such patient questionnaires as the O’Leary Sant Interstitial Cystitis Index (ICSI; FIGURE 3).¹⁰ Characteristic IC/BPS voiding frequency is 10 or more times per day (to relieve pain, not to relieve a fear of wetting, which would be expected in a patient with overactive bladder).⁸ The ICSI questionnaire
should be used primarily to establish baseline symptoms, not as a diagnostic tool. A score higher than 8 has been used as inclusion criteria for therapeutic trials, however.¹¹

 

FIGURE 2 Voiding diary9

FIGURE 3 O’Leary Sant Interstitial Cystitis Index10

It is unnecessary to primarily perform cystoscopy or urodynamics, as there are no agreed-upon diagnostic criteria for these modalities for IC/BPS. They may be considered, however, if the patient does not respond to first- and second-line therapies. Additionally, potassium sensitivity testing is painful and, in view of the paucity of benefits, the risk/benefit ratio is too high to recommend for clinical care.

Treatment: Conservative first
The treatment for IC/BPS should start with more conservative therapy (including behavioral management and physical therapy). If symptom control is inadequate, other modalities should be employed. Behavioral modifications should include:

 

• local heat/cold over the bladder and perineum
• avoidance of foods and fluids that are known to be common irritants (such as coffee and citrus)
• trial of elimination diet
• bladder training with urge suppression techniques.

As noted in FIGURE 1, first make sure that patients do not have a urinary tract infection. If culture results are negative and other criteria fit, consider the diagnosis of IC/BPS and offer therapies as outlined in the ­treat‑
ment algorithm (FIGURE 4).⁷ Repeated 
treatment for negative results of urine cultures in patients with frequency, urgency, and bladder pain can lead to unnecessary antibiotics and delayed treatment of IC/BPS.

 

7

Treatments in FIGURE 4 are ordered from most to least conservative, and initial treatment depends on symptom severity, 
clinician judgment, and patient preference. If at any point in the patient’s care the diagnosis is questioned or treatments have been ineffective, referral to a specialist, including urogynecology or urology, may be appropriate.

Managing pain
Pain management is an important component at all levels of therapy, and pharmacologic pain management principles for 
IC/BPS should be similar to those for management of other chronic pain states. Options primarily include nonsteroidal anti-
inflammatory drugs (NSAIDs) and urinary analgesics (pyridium). The use of narcotics presents the risks of tolerance and dependence. If their use is necessary, all narcotic prescriptions must come from a single source and should be used as a component of multimodality therapy to minimize narcotic use.

Interstitial cystitis (IC) is a debilitating disease that presents with a constellation of symptoms, including pain, urinary urgency, frequency, nocturia, and small voided volumes in the absence of other identifiable etiologies.¹ The overall prevalence of IC among US women is between 2.7% and 6.5%—affecting approximately 3.3 to 7.9 million women²—and it results in substantial costs^1,3 and impairments in health-related quality of life.⁴ Unfortunately, there is a lack of consensus on the pathophysiology and etiology of this prevalent and costly disorder. Thus, therapies are often empiric, with limited evidence and variable levels of improvement.⁵

There has been no clear evidence that bladder inflammation (cystitis) is involved in the etiology or pathophysiology of the condition. As a result, there has been a movement to rename it “bladder pain syndrome.” Current literature refers to the spectrum of symptoms as interstitial cystitis/bladder pain syndrome (IC/BPS).

Currently, the American Urological Association (AUA) defines IC/BPS as an unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder,
 associated with lower urinary tract symptoms of more than 6 weeks’ duration, in the absence of infection or other identifiable causes.⁶ This is still a broad, clinical diagnosis that has significant overlap with other pain syndromes but allows for treatment to begin after a relatively short symptomatic period.⁷ Because gynecologists are frequently the main care providers for women, understanding the diagnosis and treatment options for IC/BPS is important to avoid delayed treatment in a difficult to diagnose population.

Recently, the AUA published an amendment to their 2011 management guidelines to provide direction to clinicians and patients regarding how to recognize IC/BPS, conduct valid diagnostic testing, and approach treatment with the goals of maximizing symptom control and patient quality of life.⁷

In this article, we review the AUA diagnostic and treatment algorithms and the results of recently published randomized trials comparing the efficacy of various treatment modalities for IC/BPS, including pentosoan polysulfate sodium (PPS; Elmiron, Janssen Pharmaceuticals, Titusville, New Jersey) and botulinum toxin (Botox, Allergan, Irvine, California) with hydrodistension.

Evaluation and treatment algorithms for IC/BPS: AUA guidelines

Hanno PM, Erickson D, Moldwin R, Faraday MM; American Urological Association. Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment. J Urol. 2015;193(5):1545−1553.

The diagnosis of IC/BPS can be challenging due to a wide spectrum of symptoms, physical examination findings, and clinical test responses. The AUA developed its diagnostic and treatment guidelines mostly based on expert opinion, but they do provide a framework to help clinicians determine whether or not treatment for IC/BPS is warranted. The primary principles for evaluation are presented in FIGURE 1.

 

7,8

It is important to establish baseline voiding symptoms and pain levels with objective, validated instruments, including a voiding diary (FIGURE 2)⁹ and such patient questionnaires as the O’Leary Sant Interstitial Cystitis Index (ICSI; FIGURE 3).¹⁰ Characteristic IC/BPS voiding frequency is 10 or more times per day (to relieve pain, not to relieve a fear of wetting, which would be expected in a patient with overactive bladder).⁸ The ICSI questionnaire
should be used primarily to establish baseline symptoms, not as a diagnostic tool. A score higher than 8 has been used as inclusion criteria for therapeutic trials, however.¹¹

 

FIGURE 2 Voiding diary9

FIGURE 3 O’Leary Sant Interstitial Cystitis Index10

It is unnecessary to primarily perform cystoscopy or urodynamics, as there are no agreed-upon diagnostic criteria for these modalities for IC/BPS. They may be considered, however, if the patient does not respond to first- and second-line therapies. Additionally, potassium sensitivity testing is painful and, in view of the paucity of benefits, the risk/benefit ratio is too high to recommend for clinical care.

Treatment: Conservative first
The treatment for IC/BPS should start with more conservative therapy (including behavioral management and physical therapy). If symptom control is inadequate, other modalities should be employed. Behavioral modifications should include:

 

• local heat/cold over the bladder and perineum
• avoidance of foods and fluids that are known to be common irritants (such as coffee and citrus)
• trial of elimination diet
• bladder training with urge suppression techniques.

As noted in FIGURE 1, first make sure that patients do not have a urinary tract infection. If culture results are negative and other criteria fit, consider the diagnosis of IC/BPS and offer therapies as outlined in the ­treat‑
ment algorithm (FIGURE 4).⁷ Repeated 
treatment for negative results of urine cultures in patients with frequency, urgency, and bladder pain can lead to unnecessary antibiotics and delayed treatment of IC/BPS.

 

7

Treatments in FIGURE 4 are ordered from most to least conservative, and initial treatment depends on symptom severity, 
clinician judgment, and patient preference. If at any point in the patient’s care the diagnosis is questioned or treatments have been ineffective, referral to a specialist, including urogynecology or urology, may be appropriate.

Managing pain
Pain management is an important component at all levels of therapy, and pharmacologic pain management principles for 
IC/BPS should be similar to those for management of other chronic pain states. Options primarily include nonsteroidal anti-
inflammatory drugs (NSAIDs) and urinary analgesics (pyridium). The use of narcotics presents the risks of tolerance and dependence. If their use is necessary, all narcotic prescriptions must come from a single source and should be used as a component of multimodality therapy to minimize narcotic use.

Hysterectomy for benign disease is a very effective operation to treat moderate to severe uterine bleeding or pain caused by uterine problems. There are 3 main surgical approaches to performing a hysterectomy: vaginal, laparoscopic, and abdominal.

“Abdominal hysterectomy” is a term that indicates the procedure was performed using a relatively large incision in the abdominal wall. It also is possible for 2 surgical routes to be combined into one operation, such as a laparoscopically assisted vaginal hysterectomy or a laparoscopic hysterectomy with a mini-laparotomy incision to remove the uterus.

Substantial evidence indicates that vaginal and laparoscopic approaches to hysterectomy result in superior outcomes when compared with abdominal hysterectomy. In this editorial I highlight that data, as well as offer concrete ways in which we can increase the use of vaginal and laparoscopic hysterectomy while reducing the current reliance on an abdominal approach.

Vaginal and laparoscopic hysterectomy are associated with more rapid recoveryAuthors of a meta-analysis of 
47 randomized trials involving 
5,102 women concluded that women who underwent vaginal and laparoscopic hysterectomy had faster return to full activity, compared with women who had an abdominal hysterectomy. Compared with vaginal hysterectomy, the abdominal 
 approach required an additional 
12 days of postoperative recovery before return to normal activities and 
1 additional day of postoperative hospitalization.¹

In the same meta-analysis, when compared with the laparoscopic approach, abdominal hysterectomy required 15 additional days to return to normal activity and 2.6 more days of postoperative hospitalization.¹ The evidence indicates that to maximize rapid return of the patient to full activity, we should reduce the use of abdominal hysterectomy for benign disease.

Abdominal hysterectomy is the most frequent US surgical approach In the United States in 2010, the rates of hysterectomy by route were 56% abdominal, 25% laparoscopic, and 19% vaginal.² In contrast to US practice, French, German, and Australian gynecologists prioritize the vaginal route. In France in 2004, the rates of hysterectomy by route were 48% vaginal, 27% laparoscopic, and 25% abdominal.³ In Australia and Germany, vaginal hysterectomy is performed in 39% and 55% of all hysterectomy cases, respectively—a greater rate of vaginal hysterectomy than observed in the United States (TABLE 1).^4,5

Our goal should be 40% or less 
for abdominal hysterectomy. 
Based on the experience of French,³ 
Australian,⁴ and German⁵ surgeons, a realistic goal is to reduce the use of abdominal hysterectomy in the United States to a rate of 40% or less and to increase the use of vaginal and laparoscopic hysterectomy to a combined rate of 60% or more.

How will we increase vaginal and laparoscopic hysterectomy for benign disease?In order to reduce the use of abdominal hysterectomy, a multipronged effort is needed:

AAGL launches comprehensive video cooperative. A major new educational video offering on vaginal hysterectomy recently was released by the AAGL (TABLE 2).
 Produced by the AAGL and cosponsored by the American College 
of Obstetricians and Gynecologists 
and the Society of Gynecologic 
Surgeons, this resource includes detailed videos focused on basic instrumentation and technique, techniques for adnexal surgery at vaginal hysterectomy, and managing
 complications. I believe this resource will be of great value as momentum builds to increase the use of vaginal hysterectomy. In addition, OBG Management will continue to publish major articles by 
leading surgeons focused on vaginal hysterectomy.

Are you a champion of vaginal and laparoscopic hysterectomy? Every hospital should identify champions of these approaches. These master surgeons could help advance the capability of the hospital staff to confidently and safely prioritize the use of vaginal and laparoscopic hysterectomy for benign disease by mentoring other surgeons. If we reduce the use of abdominal hysterectomy we will improve outcomes and significantly advance women’s health.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Hysterectomy for benign disease is a very effective operation to treat moderate to severe uterine bleeding or pain caused by uterine problems. There are 3 main surgical approaches to performing a hysterectomy: vaginal, laparoscopic, and abdominal.

“Abdominal hysterectomy” is a term that indicates the procedure was performed using a relatively large incision in the abdominal wall. It also is possible for 2 surgical routes to be combined into one operation, such as a laparoscopically assisted vaginal hysterectomy or a laparoscopic hysterectomy with a mini-laparotomy incision to remove the uterus.

Substantial evidence indicates that vaginal and laparoscopic approaches to hysterectomy result in superior outcomes when compared with abdominal hysterectomy. In this editorial I highlight that data, as well as offer concrete ways in which we can increase the use of vaginal and laparoscopic hysterectomy while reducing the current reliance on an abdominal approach.

Vaginal and laparoscopic hysterectomy are associated with more rapid recoveryAuthors of a meta-analysis of 
47 randomized trials involving 
5,102 women concluded that women who underwent vaginal and laparoscopic hysterectomy had faster return to full activity, compared with women who had an abdominal hysterectomy. Compared with vaginal hysterectomy, the abdominal 
 approach required an additional 
12 days of postoperative recovery before return to normal activities and 
1 additional day of postoperative hospitalization.¹

In the same meta-analysis, when compared with the laparoscopic approach, abdominal hysterectomy required 15 additional days to return to normal activity and 2.6 more days of postoperative hospitalization.¹ The evidence indicates that to maximize rapid return of the patient to full activity, we should reduce the use of abdominal hysterectomy for benign disease.

Abdominal hysterectomy is the most frequent US surgical approach In the United States in 2010, the rates of hysterectomy by route were 56% abdominal, 25% laparoscopic, and 19% vaginal.² In contrast to US practice, French, German, and Australian gynecologists prioritize the vaginal route. In France in 2004, the rates of hysterectomy by route were 48% vaginal, 27% laparoscopic, and 25% abdominal.³ In Australia and Germany, vaginal hysterectomy is performed in 39% and 55% of all hysterectomy cases, respectively—a greater rate of vaginal hysterectomy than observed in the United States (TABLE 1).^4,5

Our goal should be 40% or less 
for abdominal hysterectomy. 
Based on the experience of French,³ 
Australian,⁴ and German⁵ surgeons, a realistic goal is to reduce the use of abdominal hysterectomy in the United States to a rate of 40% or less and to increase the use of vaginal and laparoscopic hysterectomy to a combined rate of 60% or more.

How will we increase vaginal and laparoscopic hysterectomy for benign disease?In order to reduce the use of abdominal hysterectomy, a multipronged effort is needed:

AAGL launches comprehensive video cooperative. A major new educational video offering on vaginal hysterectomy recently was released by the AAGL (TABLE 2).
 Produced by the AAGL and cosponsored by the American College 
of Obstetricians and Gynecologists 
and the Society of Gynecologic 
Surgeons, this resource includes detailed videos focused on basic instrumentation and technique, techniques for adnexal surgery at vaginal hysterectomy, and managing
 complications. I believe this resource will be of great value as momentum builds to increase the use of vaginal hysterectomy. In addition, OBG Management will continue to publish major articles by 
leading surgeons focused on vaginal hysterectomy.

Are you a champion of vaginal and laparoscopic hysterectomy? Every hospital should identify champions of these approaches. These master surgeons could help advance the capability of the hospital staff to confidently and safely prioritize the use of vaginal and laparoscopic hysterectomy for benign disease by mentoring other surgeons. If we reduce the use of abdominal hysterectomy we will improve outcomes and significantly advance women’s health.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Hysterectomy for benign disease is a very effective operation to treat moderate to severe uterine bleeding or pain caused by uterine problems. There are 3 main surgical approaches to performing a hysterectomy: vaginal, laparoscopic, and abdominal.

“Abdominal hysterectomy” is a term that indicates the procedure was performed using a relatively large incision in the abdominal wall. It also is possible for 2 surgical routes to be combined into one operation, such as a laparoscopically assisted vaginal hysterectomy or a laparoscopic hysterectomy with a mini-laparotomy incision to remove the uterus.

Substantial evidence indicates that vaginal and laparoscopic approaches to hysterectomy result in superior outcomes when compared with abdominal hysterectomy. In this editorial I highlight that data, as well as offer concrete ways in which we can increase the use of vaginal and laparoscopic hysterectomy while reducing the current reliance on an abdominal approach.

Vaginal and laparoscopic hysterectomy are associated with more rapid recoveryAuthors of a meta-analysis of 
47 randomized trials involving 
5,102 women concluded that women who underwent vaginal and laparoscopic hysterectomy had faster return to full activity, compared with women who had an abdominal hysterectomy. Compared with vaginal hysterectomy, the abdominal 
 approach required an additional 
12 days of postoperative recovery before return to normal activities and 
1 additional day of postoperative hospitalization.¹

In the same meta-analysis, when compared with the laparoscopic approach, abdominal hysterectomy required 15 additional days to return to normal activity and 2.6 more days of postoperative hospitalization.¹ The evidence indicates that to maximize rapid return of the patient to full activity, we should reduce the use of abdominal hysterectomy for benign disease.

Abdominal hysterectomy is the most frequent US surgical approach In the United States in 2010, the rates of hysterectomy by route were 56% abdominal, 25% laparoscopic, and 19% vaginal.² In contrast to US practice, French, German, and Australian gynecologists prioritize the vaginal route. In France in 2004, the rates of hysterectomy by route were 48% vaginal, 27% laparoscopic, and 25% abdominal.³ In Australia and Germany, vaginal hysterectomy is performed in 39% and 55% of all hysterectomy cases, respectively—a greater rate of vaginal hysterectomy than observed in the United States (TABLE 1).^4,5

Our goal should be 40% or less 
for abdominal hysterectomy. 
Based on the experience of French,³ 
Australian,⁴ and German⁵ surgeons, a realistic goal is to reduce the use of abdominal hysterectomy in the United States to a rate of 40% or less and to increase the use of vaginal and laparoscopic hysterectomy to a combined rate of 60% or more.

How will we increase vaginal and laparoscopic hysterectomy for benign disease?In order to reduce the use of abdominal hysterectomy, a multipronged effort is needed:

AAGL launches comprehensive video cooperative. A major new educational video offering on vaginal hysterectomy recently was released by the AAGL (TABLE 2).
 Produced by the AAGL and cosponsored by the American College 
of Obstetricians and Gynecologists 
and the Society of Gynecologic 
Surgeons, this resource includes detailed videos focused on basic instrumentation and technique, techniques for adnexal surgery at vaginal hysterectomy, and managing
 complications. I believe this resource will be of great value as momentum builds to increase the use of vaginal hysterectomy. In addition, OBG Management will continue to publish major articles by 
leading surgeons focused on vaginal hysterectomy.

Are you a champion of vaginal and laparoscopic hysterectomy? Every hospital should identify champions of these approaches. These master surgeons could help advance the capability of the hospital staff to confidently and safely prioritize the use of vaginal and laparoscopic hysterectomy for benign disease by mentoring other surgeons. If we reduce the use of abdominal hysterectomy we will improve outcomes and significantly advance women’s health.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

In this article, I describe my technique for a vaginal approach to right salpingectomy with ovarian preservation, as well as right salpingo-oophorectomy, in a patient lacking a left tube and ovary. This technique is fully illustrated on a cadaver in the Web-based master course in vaginal hysterectomy produced by the AAGL and co-sponsored by the American College of Obstetricians and Gynecologists and the Society of Gynecologic Surgeons. That course is available online at https://www.aagl.org/vaghystwebinar.

For a detailed description of vaginal hysterectomy technique, see the article entitled “Vaginal hysterectomy using basic instrumentation,” by Barbara S. Levy, MD, which appeared in the October 2015 issue of 
OBG Management. Next month, in the December 2015 issue of the journal, I will detail my strategies for managing complications associated with vaginal hysterectomy, salpingectomy, and salpingo-oophorectomy.

Right salpingectomy

FIGURE 1 Locate the tube

The fallopian tube will almost always be found on top of the ovary.

FIGURE 2 Isolate the tube

Grasp the tube and bring it to the midline.

Start with light traction
Begin by placing an instrument on the round ligament, tube, and uterine-ovarian pedicle, exerting light traction. Note that the tube will always be found on top of the ovary 
(FIGURE 1). Take care during placement of packing material to avoid sweeping the fimbriae of the tube up and out of the surgical field. You may need to play with the packing a bit until you are able to deliver the tube.

Once you identify the tube, isolate it by bringing it down to the midline 
(FIGURE 2). One thing to note if 
you’re accustomed to performing bilateral salpingo-oophorectomy: The gonadal pedicle is fairly substantive and can sustain a bit of tugging. However, if you’re performing salpingectomy with ovarian preservation, you need to be much more careful in your handling of the tube because the mesosalpinx is extremely delicate.

After you bring the tube to the midline, grasp it using a Heaney or Shallcross clamp. You could use energy to take this pedicle or clamp and tie it.

Make sure that the packing material is out of the way and that you have most of the tube nicely isolated. Don’t take the tube too far up in the surgical field because, if you lose it, it can be hard to control the bleeding. Ensure that you have grasped the fimbriated end of the tube.

In some cases you can leave a portion of the tube right next to the round ligament (FIGURE 3). You can go back and take that portion later, if you desire. But when it comes to the potential for the fallopian tube to generate carcinoma, most of the concern involves the mid to distal end of the tube rather than the cornual portion.

Once the Shallcross clamp has a good purchase on the pedicle, bring the suture around the clamp and then pass it under the tube so that you encircle the mesosalpinx pedicle (FIGURE 4). It is extremely important during salpingectomy to tie this suture down gently but tightly. In the process, have your assistant flash the Shallcross clamp open when you tie the suture. Otherwise, the suture will tend to tear through the mesosalpinx. Be very careful in your handling of the specimen at this point. Next, cut right along the edge of the clamp to remove the tube.

FIGURE 3 Focus on the distal tube		FIGURE 4 Clamp and tie the pedicle
The cornual portion of the tube (proximal to the round ligament) can be left behind, if desired. The propensity for cancer centers on the distal end of the tube.		Bring the suture around the clamp and then pass it under the tube so that you encircle the mesosalpinx pedicle.

If you prefer, you can stick-tie the remaining portion again, but usually one tie will suffice because there is such a small pedicle there. The distal portion of the pedicle eventually will necrose close to the tie. The next step is ensuring hemostasis.

On occasion, if you lose the pedicle high in the surgical field, you can try to oversew it. A 2-0 Vicryl suture may be used to place a figure-eight stitch to control bleeding around the mesosalpinx. Alternatively, an energy device may be used for hemostasis. Rarely, if you encounter bleeding that does not respond to the previous suggestions, you may need to remove the ovary to control bleeding if the tissue tears.

Transvaginal technique for salpingo-oophorectomy

Once the hysterectomy is completed, grasp the round ligament, tube, and uterine-ovarian pedicle, placing slight tension on the pedicle, and free the right round ligament to ease isolation of the gonadal vessels. Using electrocautery, carefully transect the round ligament. It is critical when isolating the round ligament to transect only the ligament and not to get deep into the underlying tissue or bleeding will ensue. If you “hug” just the round ligament, you will open into the broad ligament and easily be able to isolate the gonadal pedicle.

Once the pedicle is nicely isolated, readjust your retractors or lighting to improve visualization. Now the gonadal vessels can be isolated up high much more easily (FIGURE 1).

Next, use a Heaney clamp to grab the pedicle, making sure that the ovary is medial to the clamp (FIGURE 2).

FIGURE 1: ISOLATE THE GONADAL VESSELS Once optimal visualization is achieved, the gonadal vessels can be isolated easily.		FIGURE 2: KEEP THE OVARY MEDIAL TO THE CLAMP  Use a Heaney clamp to grab the pedicle, keeping the ovary medial to the clamp.

In this setting, there are a number of techniques you can use to complete the salpingo-oophorectomy. I tend to doubly ligate the pedicle. To begin, cut the tagging suture to get it out of the way. Then place a free tie lateral to the clamp, bringing it down and underneath to fully encircle the pedicle. Ligate the pedicle then cut the free tie. Follow by cutting the pedicle beside the Heaney clamp and removing the specimen. Stick-tie the remaining pedicle.

Locate the free tie, which is easily identified. Place your needle between that free tie and the clamp so that you do not pierce the vessels proximal to the tie with that needle. Then doubly ligate the pedicle.

Check for hemostasis and, once confirmed, cut the pedicle tie. Because this patient does not have a left tube and ovary, the procedure is now completed.

Conclusion

The tubes are usually readily accessible for removal at the time of vaginal hysterectomy. There is evolving evidence that the tube may play a role in malignancy of the female genital tract. Thus, removal may be preventive. In addition, if there are paratubal cysts or hydrosalpinx from prior tubal ligation, it makes sense to remove the tube. There is little evidence to suggest that removal of the tubes accelerates the menopausal transition due to compromise of the blood supply to the ovaries.

You must be very gentle when handling and removing just the tubes. The mesosalpinx is delicate and easily torn or traumatized. A careful and deliberate approach is warranted.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

In this article, I describe my technique for a vaginal approach to right salpingectomy with ovarian preservation, as well as right salpingo-oophorectomy, in a patient lacking a left tube and ovary. This technique is fully illustrated on a cadaver in the Web-based master course in vaginal hysterectomy produced by the AAGL and co-sponsored by the American College of Obstetricians and Gynecologists and the Society of Gynecologic Surgeons. That course is available online at https://www.aagl.org/vaghystwebinar.

For a detailed description of vaginal hysterectomy technique, see the article entitled “Vaginal hysterectomy using basic instrumentation,” by Barbara S. Levy, MD, which appeared in the October 2015 issue of 
OBG Management. Next month, in the December 2015 issue of the journal, I will detail my strategies for managing complications associated with vaginal hysterectomy, salpingectomy, and salpingo-oophorectomy.

Right salpingectomy

FIGURE 1 Locate the tube

The fallopian tube will almost always be found on top of the ovary.

FIGURE 2 Isolate the tube

Grasp the tube and bring it to the midline.

Start with light traction
Begin by placing an instrument on the round ligament, tube, and uterine-ovarian pedicle, exerting light traction. Note that the tube will always be found on top of the ovary 
(FIGURE 1). Take care during placement of packing material to avoid sweeping the fimbriae of the tube up and out of the surgical field. You may need to play with the packing a bit until you are able to deliver the tube.

Once you identify the tube, isolate it by bringing it down to the midline 
(FIGURE 2). One thing to note if 
you’re accustomed to performing bilateral salpingo-oophorectomy: The gonadal pedicle is fairly substantive and can sustain a bit of tugging. However, if you’re performing salpingectomy with ovarian preservation, you need to be much more careful in your handling of the tube because the mesosalpinx is extremely delicate.

After you bring the tube to the midline, grasp it using a Heaney or Shallcross clamp. You could use energy to take this pedicle or clamp and tie it.

Make sure that the packing material is out of the way and that you have most of the tube nicely isolated. Don’t take the tube too far up in the surgical field because, if you lose it, it can be hard to control the bleeding. Ensure that you have grasped the fimbriated end of the tube.

In some cases you can leave a portion of the tube right next to the round ligament (FIGURE 3). You can go back and take that portion later, if you desire. But when it comes to the potential for the fallopian tube to generate carcinoma, most of the concern involves the mid to distal end of the tube rather than the cornual portion.

Once the Shallcross clamp has a good purchase on the pedicle, bring the suture around the clamp and then pass it under the tube so that you encircle the mesosalpinx pedicle (FIGURE 4). It is extremely important during salpingectomy to tie this suture down gently but tightly. In the process, have your assistant flash the Shallcross clamp open when you tie the suture. Otherwise, the suture will tend to tear through the mesosalpinx. Be very careful in your handling of the specimen at this point. Next, cut right along the edge of the clamp to remove the tube.

FIGURE 3 Focus on the distal tube		FIGURE 4 Clamp and tie the pedicle
The cornual portion of the tube (proximal to the round ligament) can be left behind, if desired. The propensity for cancer centers on the distal end of the tube.		Bring the suture around the clamp and then pass it under the tube so that you encircle the mesosalpinx pedicle.

If you prefer, you can stick-tie the remaining portion again, but usually one tie will suffice because there is such a small pedicle there. The distal portion of the pedicle eventually will necrose close to the tie. The next step is ensuring hemostasis.

On occasion, if you lose the pedicle high in the surgical field, you can try to oversew it. A 2-0 Vicryl suture may be used to place a figure-eight stitch to control bleeding around the mesosalpinx. Alternatively, an energy device may be used for hemostasis. Rarely, if you encounter bleeding that does not respond to the previous suggestions, you may need to remove the ovary to control bleeding if the tissue tears.

Transvaginal technique for salpingo-oophorectomy

Once the hysterectomy is completed, grasp the round ligament, tube, and uterine-ovarian pedicle, placing slight tension on the pedicle, and free the right round ligament to ease isolation of the gonadal vessels. Using electrocautery, carefully transect the round ligament. It is critical when isolating the round ligament to transect only the ligament and not to get deep into the underlying tissue or bleeding will ensue. If you “hug” just the round ligament, you will open into the broad ligament and easily be able to isolate the gonadal pedicle.

Once the pedicle is nicely isolated, readjust your retractors or lighting to improve visualization. Now the gonadal vessels can be isolated up high much more easily (FIGURE 1).

Next, use a Heaney clamp to grab the pedicle, making sure that the ovary is medial to the clamp (FIGURE 2).

FIGURE 1: ISOLATE THE GONADAL VESSELS Once optimal visualization is achieved, the gonadal vessels can be isolated easily.		FIGURE 2: KEEP THE OVARY MEDIAL TO THE CLAMP  Use a Heaney clamp to grab the pedicle, keeping the ovary medial to the clamp.

In this setting, there are a number of techniques you can use to complete the salpingo-oophorectomy. I tend to doubly ligate the pedicle. To begin, cut the tagging suture to get it out of the way. Then place a free tie lateral to the clamp, bringing it down and underneath to fully encircle the pedicle. Ligate the pedicle then cut the free tie. Follow by cutting the pedicle beside the Heaney clamp and removing the specimen. Stick-tie the remaining pedicle.

Locate the free tie, which is easily identified. Place your needle between that free tie and the clamp so that you do not pierce the vessels proximal to the tie with that needle. Then doubly ligate the pedicle.

Check for hemostasis and, once confirmed, cut the pedicle tie. Because this patient does not have a left tube and ovary, the procedure is now completed.

Conclusion

The tubes are usually readily accessible for removal at the time of vaginal hysterectomy. There is evolving evidence that the tube may play a role in malignancy of the female genital tract. Thus, removal may be preventive. In addition, if there are paratubal cysts or hydrosalpinx from prior tubal ligation, it makes sense to remove the tube. There is little evidence to suggest that removal of the tubes accelerates the menopausal transition due to compromise of the blood supply to the ovaries.

You must be very gentle when handling and removing just the tubes. The mesosalpinx is delicate and easily torn or traumatized. A careful and deliberate approach is warranted.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

In this article, I describe my technique for a vaginal approach to right salpingectomy with ovarian preservation, as well as right salpingo-oophorectomy, in a patient lacking a left tube and ovary. This technique is fully illustrated on a cadaver in the Web-based master course in vaginal hysterectomy produced by the AAGL and co-sponsored by the American College of Obstetricians and Gynecologists and the Society of Gynecologic Surgeons. That course is available online at https://www.aagl.org/vaghystwebinar.

For a detailed description of vaginal hysterectomy technique, see the article entitled “Vaginal hysterectomy using basic instrumentation,” by Barbara S. Levy, MD, which appeared in the October 2015 issue of 
OBG Management. Next month, in the December 2015 issue of the journal, I will detail my strategies for managing complications associated with vaginal hysterectomy, salpingectomy, and salpingo-oophorectomy.

Right salpingectomy

FIGURE 1 Locate the tube

The fallopian tube will almost always be found on top of the ovary.

FIGURE 2 Isolate the tube

Grasp the tube and bring it to the midline.

Start with light traction
Begin by placing an instrument on the round ligament, tube, and uterine-ovarian pedicle, exerting light traction. Note that the tube will always be found on top of the ovary 
(FIGURE 1). Take care during placement of packing material to avoid sweeping the fimbriae of the tube up and out of the surgical field. You may need to play with the packing a bit until you are able to deliver the tube.

Once you identify the tube, isolate it by bringing it down to the midline 
(FIGURE 2). One thing to note if 
you’re accustomed to performing bilateral salpingo-oophorectomy: The gonadal pedicle is fairly substantive and can sustain a bit of tugging. However, if you’re performing salpingectomy with ovarian preservation, you need to be much more careful in your handling of the tube because the mesosalpinx is extremely delicate.

After you bring the tube to the midline, grasp it using a Heaney or Shallcross clamp. You could use energy to take this pedicle or clamp and tie it.

Make sure that the packing material is out of the way and that you have most of the tube nicely isolated. Don’t take the tube too far up in the surgical field because, if you lose it, it can be hard to control the bleeding. Ensure that you have grasped the fimbriated end of the tube.

In some cases you can leave a portion of the tube right next to the round ligament (FIGURE 3). You can go back and take that portion later, if you desire. But when it comes to the potential for the fallopian tube to generate carcinoma, most of the concern involves the mid to distal end of the tube rather than the cornual portion.

Once the Shallcross clamp has a good purchase on the pedicle, bring the suture around the clamp and then pass it under the tube so that you encircle the mesosalpinx pedicle (FIGURE 4). It is extremely important during salpingectomy to tie this suture down gently but tightly. In the process, have your assistant flash the Shallcross clamp open when you tie the suture. Otherwise, the suture will tend to tear through the mesosalpinx. Be very careful in your handling of the specimen at this point. Next, cut right along the edge of the clamp to remove the tube.

FIGURE 3 Focus on the distal tube		FIGURE 4 Clamp and tie the pedicle
The cornual portion of the tube (proximal to the round ligament) can be left behind, if desired. The propensity for cancer centers on the distal end of the tube.		Bring the suture around the clamp and then pass it under the tube so that you encircle the mesosalpinx pedicle.

If you prefer, you can stick-tie the remaining portion again, but usually one tie will suffice because there is such a small pedicle there. The distal portion of the pedicle eventually will necrose close to the tie. The next step is ensuring hemostasis.

On occasion, if you lose the pedicle high in the surgical field, you can try to oversew it. A 2-0 Vicryl suture may be used to place a figure-eight stitch to control bleeding around the mesosalpinx. Alternatively, an energy device may be used for hemostasis. Rarely, if you encounter bleeding that does not respond to the previous suggestions, you may need to remove the ovary to control bleeding if the tissue tears.

Transvaginal technique for salpingo-oophorectomy

Once the hysterectomy is completed, grasp the round ligament, tube, and uterine-ovarian pedicle, placing slight tension on the pedicle, and free the right round ligament to ease isolation of the gonadal vessels. Using electrocautery, carefully transect the round ligament. It is critical when isolating the round ligament to transect only the ligament and not to get deep into the underlying tissue or bleeding will ensue. If you “hug” just the round ligament, you will open into the broad ligament and easily be able to isolate the gonadal pedicle.

Once the pedicle is nicely isolated, readjust your retractors or lighting to improve visualization. Now the gonadal vessels can be isolated up high much more easily (FIGURE 1).

Next, use a Heaney clamp to grab the pedicle, making sure that the ovary is medial to the clamp (FIGURE 2).

FIGURE 1: ISOLATE THE GONADAL VESSELS Once optimal visualization is achieved, the gonadal vessels can be isolated easily.		FIGURE 2: KEEP THE OVARY MEDIAL TO THE CLAMP  Use a Heaney clamp to grab the pedicle, keeping the ovary medial to the clamp.

In this setting, there are a number of techniques you can use to complete the salpingo-oophorectomy. I tend to doubly ligate the pedicle. To begin, cut the tagging suture to get it out of the way. Then place a free tie lateral to the clamp, bringing it down and underneath to fully encircle the pedicle. Ligate the pedicle then cut the free tie. Follow by cutting the pedicle beside the Heaney clamp and removing the specimen. Stick-tie the remaining pedicle.

Locate the free tie, which is easily identified. Place your needle between that free tie and the clamp so that you do not pierce the vessels proximal to the tie with that needle. Then doubly ligate the pedicle.

Check for hemostasis and, once confirmed, cut the pedicle tie. Because this patient does not have a left tube and ovary, the procedure is now completed.

Conclusion

The tubes are usually readily accessible for removal at the time of vaginal hysterectomy. There is evolving evidence that the tube may play a role in malignancy of the female genital tract. Thus, removal may be preventive. In addition, if there are paratubal cysts or hydrosalpinx from prior tubal ligation, it makes sense to remove the tube. There is little evidence to suggest that removal of the tubes accelerates the menopausal transition due to compromise of the blood supply to the ovaries.

You must be very gentle when handling and removing just the tubes. The mesosalpinx is delicate and easily torn or traumatized. A careful and deliberate approach is warranted.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

It was a long road to approval by the US Food and Drug Administration (FDA), but flibanserin (Addyi) got the nod on 
August 18, 2015. Its New Drug Application (NDA) originally was filed October 27, 2009. The drug launched October 17, 2015.

Although there has been a lot of fanfare about approval of this drug, most of the coverage has focused on its status as the “first female Viagra”—a less than accurate depiction. For a more realistic and practical assessment of the drug, OBG Management turned to Michael Krychman, MD, executive director of the Southern California Center for Sexual Health and Survivorship Medicine in Newport Beach, to determine the types of information clinicians need to know to begin prescribing flibanserin. This article highlights 11 questions (and answers) to help you get started.

1. How did the FDA arrive 
at its approval?
In 2012, the agency determined that female sexual dysfunction was one of 20 disease areas that warranted focused attention. In October 2014, as part of its intensified look at female sexual dysfunction, the FDA convened a 2-day meeting “to advance our understanding,” reports Andrea Fischer, FDA press officer.

“During the first day of the meeting, the FDA solicited patients’ perspectives on their condition and its impact on daily life. While this meeting did not focus on flibanserin, it provided an opportunity for the FDA to hear directly from patients about the impact of their condition,” Ms. Fischer says. During the second day of the meeting, the FDA “discussed scientific issues and challenges with experts in sexual medicine.”

As a result, by the time of the FDA’s 
June 4, 2015 Advisory Committee meeting on the flibanserin NDA, FDA physician-scientists were well versed in many nuances of female sexual function. That meeting included an open public hearing “that provided an opportunity for members of the public, including patients, to provide input specifically on the flibanserin application,” Ms. Fischer notes.

Nuances of the deliberations
“The FDA’s regulatory decision making on any drug product is a science-based process that carefully weighs each drug in terms of its risks and benefits to the patient population for which the drug would be indicated,” says Ms. Fischer.

The challenge in the case of flibanserin was determining whether the drug provides “clinically meaningful” improvements in sexual activity and desire.

“For many conditions and diseases, what constitutes ‘clinically meaningful’ is well known and accepted,” Ms. Fischer notes, “such as when something is cured or a severe symptom that is life-altering resolves completely. For others, this is not the case. For example, a condition that has a wide range of degree of severity can offer challenges in assessing what constitutes a clinically meaningful treatment effect. Ascertaining this requires a comprehensive knowledge of the disease, affected patient population, management strategies and the drug in question, as well as an ability to look at the clinical trial data taking this all into account.”

“In clinical trials, an important method for assessing the impact of a treatment on a patient’s symptoms, mental state, or functional status is through direct self-report using well developed and thoughtfully integrated patient-reported outcome (PRO) assessments,” Ms. Fischer says. “PROs can provide valuable information on the patient perspective when determining whether benefits outweigh risks, and they also are used to support medical product labeling claims, which are a key source of information for both health care providers and patients. PROs have been and continue to be a high priority as part of FDA’s commitment to advance patient-focused drug development, and we fully expect this to continue. The clinical trials in the flibanserin NDA all utilized PRO assessments.”

Those assessments found that patients taking flibanserin had a significant increase in “sexually satisfying events.” Three 24-week randomized controlled trials explored this endpoint for flibanserin (studies 1–3).

As for improvements in desire, the first 
2 trials utilized an e-diary to assess this aspect of sexual function, while the 3rd trial utilized the Female Sexual Function Index (FSFI).

Although the e-diary reflected no statistically significant improvement in desire in the first 2 trials, the FSFI did find significant improvement in the 3rd trial. In addition, when the FSFI was considered across all 3 trials, results in the desire domain were consistent. (The FSFI was used as a secondary tool in the first 2 trials.)

In addition, sexual distress, as measured by the Female Sexual Distress Scale (FSDS), was decreased in the trials with use of flibanserin, notes Dr. Krychman. The Advisory 
Committee determined that these findings were sufficient to demonstrate clinically meaningful improvements with use of the drug.

Although the drug was approved by the FDA, the agency was sufficiently concerned about some of its potential risks (see questions 4 and 5) that it implemented rigorous mitigation strategies (see question 7). Additional investigations were requested by the agency, including drug-drug interaction, alcohol challenge, and driving studies.

2. What are the indications?
Flibanserin is intended for use in premenopausal women who have acquired, generalized hypoactive sexual desire disorder (HSDD). That diagnosis no longer is included in the 5th edition of the Diagnostic and 
Statistical Manual of Mental Disorders but is described in drug package labeling as “low sexual desire that causes marked distress or interpersonal difficulty and is not due to:

Although the drug has been tested in both premenopausal and postmenopausal women, it was approved for use only in premenopausal women. Also note inclusion of the term “acquired” before the diagnosis of HSDD, indicating that the drug is inappropriate for women who have never experienced a period of normal sexual desire.

3. How is HSDD diagnosed?
One of the best screening tools is the 
Decreased Sexual Desire Screener, says 
Dr. Krychman. It is available at http://obgynalliance.com/files/fsd/DSDS_Pocketcard.pdf. This tool is a validated instrument to help clinicians identify what HSDD is and is not.

4. Does the drug carry 
any warnings?
Yes, it carries a black box warning about the risks of hypotension and syncope:

5. Are there any other risks worth noting?
The medication can increase the risks of hypotension and syncope even without concomitant use of alcohol. For example, in clinical trials, hypotension was reported in 0.2% of flibanserin-treated women versus less than 0.1% of placebo users. And syncope was reported in 0.4% of flibanserin users versus 0.2% of placebo-treated patients. Flibanserin is prescribed as a once-daily medication that is to be taken at bedtime; the risks of hypotension and syncope are increased if flibanserin is taken during waking hours.

The risk of adverse effects when flibanserin is taken with alcohol is highlighted by one case reported in package labeling: A 54-year-old postmenopausal woman died after taking flibanserin (100 mg daily at bedtime) for 14 days. This patient had a history of hypertension and hypercholesterolemia and consumed a baseline amount of 1 to 3 alcoholic beverages daily. She died of acute alcohol intoxication, with a blood alcohol concentration of 0.289 g/dL.¹ Whether this patient’s death was related to flibanserin use is unknown.¹

It is interesting to note that, in the studies of flibanserin leading up to the drug’s 
approval, alcohol use was not an exclusion, says Dr. Krychman. “Approximately 58% of women were self-described as mild to moderate drinkers. The clinical program was extremely large—more than 11,000 women were studied.”

Flibanserin is currently not approved for use in postmenopausal women, and concomitant alcohol consumption is contraindicated.

6. What is the dose?
The recommended dose is one tablet of 
100 mg daily. The drug is to be taken at 
bedtime to reduce the risks of hypotension, syncope, accidental injury, and central nervous system (CNS) depression, which can occur even in the absence of alcohol.

7. Are there any requirements for clinicians who want to prescribe the drug?
Yes. Because of the risks of hypotension, syncope, and CNS depression, the drug is subject to Risk Evaluation and Mitigation Strategies (REMS), as determined by the FDA. To prescribe the drug, providers must:

Before giving a patient her initial prescription, the provider must counsel her about the risks of hypotension and syncope and the interaction with alcohol using the Patient-Provider Agreement Form. The provider must then complete that form, provide a designated portion of it to the patient, and retain the remainder for the patient’s file.

For more information and to download the relevant forms, visit https://www.addyirems.com.

8. What are the most common 
adverse reactions to the drug?
According to package labeling, the most common adverse reactions, with an incidence greater than 2%, are dizziness, somnolence, nausea, fatigue, insomnia, and dry mouth.

Less common reactions include anxiety, constipation, abdominal pain, rash, sedation, and vertigo.

In studies of the drug, appendicitis was reported among 0.2% of flibanserin-treated patients, compared with no reports of appendicitis among placebo-treated patients. The FDA has requested additional investigation of the association, if any, between flibanserin 
and appendicitis.

9. What drug interactions are notable?
As stated earlier, the concomitant use of flibanserin with alcohol or a moderate or strong CYP3A4 inhibitor can result in severe hypotension and syncope. Flibanserin also should not be prescribed for patients who use other CNS depressants such as diphenhydramine, opioids, benzodiazepines, and hypnotic agents.

Some examples of strong CYP3A4 inhibitors are ketoconazole, itraconazole, posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin, and conivaptan.

Moderate CYP3A4 inhibitors include amprenavir, atazanavir, ciprofloxacin, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, and grapefruit juice.

In addition, the concomitant use of flibanserin with multiple weak CYP3A4 inhibitors—which include herbal supplements such as ginkgo and resveratrol and nonprescription drugs such as cimetidine—also may increase the risks of hypotension and syncope.

The concomitant use of flibanserin with digoxin increases the digoxin concentration and may lead to toxicity.

10. Is the drug safe in pregnancy 
and lactation?
There are currently no data on the use of flibanserin in human pregnancy. In animals, fetal toxicity occurred only in the presence of significant maternal toxicity. Adverse effects included decreased fetal weight, structural anomalies, and increases in fetal loss when exposure exceeded 15 times the recommended human dosage.

As for the advisability of using flibanserin during lactation, it is unknown whether the drug is excreted in human milk, whether it might have adverse effects in the breastfed infant, or whether it affects milk production. Package labeling states: “Because of the potential for serious adverse reactions, including sedation in a breastfed infant, breastfeeding is not recommended during treatment with [flibanserin].”¹

11. When should the drug 
be discontinued?
If there is no improvement in sexual desire after an 8-week trial of flibanserin, the drug should be 
discontinued.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

It was a long road to approval by the US Food and Drug Administration (FDA), but flibanserin (Addyi) got the nod on 
August 18, 2015. Its New Drug Application (NDA) originally was filed October 27, 2009. The drug launched October 17, 2015.

Although there has been a lot of fanfare about approval of this drug, most of the coverage has focused on its status as the “first female Viagra”—a less than accurate depiction. For a more realistic and practical assessment of the drug, OBG Management turned to Michael Krychman, MD, executive director of the Southern California Center for Sexual Health and Survivorship Medicine in Newport Beach, to determine the types of information clinicians need to know to begin prescribing flibanserin. This article highlights 11 questions (and answers) to help you get started.

1. How did the FDA arrive 
at its approval?
In 2012, the agency determined that female sexual dysfunction was one of 20 disease areas that warranted focused attention. In October 2014, as part of its intensified look at female sexual dysfunction, the FDA convened a 2-day meeting “to advance our understanding,” reports Andrea Fischer, FDA press officer.

“During the first day of the meeting, the FDA solicited patients’ perspectives on their condition and its impact on daily life. While this meeting did not focus on flibanserin, it provided an opportunity for the FDA to hear directly from patients about the impact of their condition,” Ms. Fischer says. During the second day of the meeting, the FDA “discussed scientific issues and challenges with experts in sexual medicine.”

As a result, by the time of the FDA’s 
June 4, 2015 Advisory Committee meeting on the flibanserin NDA, FDA physician-scientists were well versed in many nuances of female sexual function. That meeting included an open public hearing “that provided an opportunity for members of the public, including patients, to provide input specifically on the flibanserin application,” Ms. Fischer notes.

Nuances of the deliberations
“The FDA’s regulatory decision making on any drug product is a science-based process that carefully weighs each drug in terms of its risks and benefits to the patient population for which the drug would be indicated,” says Ms. Fischer.

The challenge in the case of flibanserin was determining whether the drug provides “clinically meaningful” improvements in sexual activity and desire.

“For many conditions and diseases, what constitutes ‘clinically meaningful’ is well known and accepted,” Ms. Fischer notes, “such as when something is cured or a severe symptom that is life-altering resolves completely. For others, this is not the case. For example, a condition that has a wide range of degree of severity can offer challenges in assessing what constitutes a clinically meaningful treatment effect. Ascertaining this requires a comprehensive knowledge of the disease, affected patient population, management strategies and the drug in question, as well as an ability to look at the clinical trial data taking this all into account.”

“In clinical trials, an important method for assessing the impact of a treatment on a patient’s symptoms, mental state, or functional status is through direct self-report using well developed and thoughtfully integrated patient-reported outcome (PRO) assessments,” Ms. Fischer says. “PROs can provide valuable information on the patient perspective when determining whether benefits outweigh risks, and they also are used to support medical product labeling claims, which are a key source of information for both health care providers and patients. PROs have been and continue to be a high priority as part of FDA’s commitment to advance patient-focused drug development, and we fully expect this to continue. The clinical trials in the flibanserin NDA all utilized PRO assessments.”

Those assessments found that patients taking flibanserin had a significant increase in “sexually satisfying events.” Three 24-week randomized controlled trials explored this endpoint for flibanserin (studies 1–3).

As for improvements in desire, the first 
2 trials utilized an e-diary to assess this aspect of sexual function, while the 3rd trial utilized the Female Sexual Function Index (FSFI).

Although the e-diary reflected no statistically significant improvement in desire in the first 2 trials, the FSFI did find significant improvement in the 3rd trial. In addition, when the FSFI was considered across all 3 trials, results in the desire domain were consistent. (The FSFI was used as a secondary tool in the first 2 trials.)

In addition, sexual distress, as measured by the Female Sexual Distress Scale (FSDS), was decreased in the trials with use of flibanserin, notes Dr. Krychman. The Advisory 
Committee determined that these findings were sufficient to demonstrate clinically meaningful improvements with use of the drug.

Although the drug was approved by the FDA, the agency was sufficiently concerned about some of its potential risks (see questions 4 and 5) that it implemented rigorous mitigation strategies (see question 7). Additional investigations were requested by the agency, including drug-drug interaction, alcohol challenge, and driving studies.

2. What are the indications?
Flibanserin is intended for use in premenopausal women who have acquired, generalized hypoactive sexual desire disorder (HSDD). That diagnosis no longer is included in the 5th edition of the Diagnostic and 
Statistical Manual of Mental Disorders but is described in drug package labeling as “low sexual desire that causes marked distress or interpersonal difficulty and is not due to:

Although the drug has been tested in both premenopausal and postmenopausal women, it was approved for use only in premenopausal women. Also note inclusion of the term “acquired” before the diagnosis of HSDD, indicating that the drug is inappropriate for women who have never experienced a period of normal sexual desire.

3. How is HSDD diagnosed?
One of the best screening tools is the 
Decreased Sexual Desire Screener, says 
Dr. Krychman. It is available at http://obgynalliance.com/files/fsd/DSDS_Pocketcard.pdf. This tool is a validated instrument to help clinicians identify what HSDD is and is not.

4. Does the drug carry 
any warnings?
Yes, it carries a black box warning about the risks of hypotension and syncope:

5. Are there any other risks worth noting?
The medication can increase the risks of hypotension and syncope even without concomitant use of alcohol. For example, in clinical trials, hypotension was reported in 0.2% of flibanserin-treated women versus less than 0.1% of placebo users. And syncope was reported in 0.4% of flibanserin users versus 0.2% of placebo-treated patients. Flibanserin is prescribed as a once-daily medication that is to be taken at bedtime; the risks of hypotension and syncope are increased if flibanserin is taken during waking hours.

The risk of adverse effects when flibanserin is taken with alcohol is highlighted by one case reported in package labeling: A 54-year-old postmenopausal woman died after taking flibanserin (100 mg daily at bedtime) for 14 days. This patient had a history of hypertension and hypercholesterolemia and consumed a baseline amount of 1 to 3 alcoholic beverages daily. She died of acute alcohol intoxication, with a blood alcohol concentration of 0.289 g/dL.¹ Whether this patient’s death was related to flibanserin use is unknown.¹

It is interesting to note that, in the studies of flibanserin leading up to the drug’s 
approval, alcohol use was not an exclusion, says Dr. Krychman. “Approximately 58% of women were self-described as mild to moderate drinkers. The clinical program was extremely large—more than 11,000 women were studied.”

Flibanserin is currently not approved for use in postmenopausal women, and concomitant alcohol consumption is contraindicated.

6. What is the dose?
The recommended dose is one tablet of 
100 mg daily. The drug is to be taken at 
bedtime to reduce the risks of hypotension, syncope, accidental injury, and central nervous system (CNS) depression, which can occur even in the absence of alcohol.

7. Are there any requirements for clinicians who want to prescribe the drug?
Yes. Because of the risks of hypotension, syncope, and CNS depression, the drug is subject to Risk Evaluation and Mitigation Strategies (REMS), as determined by the FDA. To prescribe the drug, providers must:

Before giving a patient her initial prescription, the provider must counsel her about the risks of hypotension and syncope and the interaction with alcohol using the Patient-Provider Agreement Form. The provider must then complete that form, provide a designated portion of it to the patient, and retain the remainder for the patient’s file.

For more information and to download the relevant forms, visit https://www.addyirems.com.

8. What are the most common 
adverse reactions to the drug?
According to package labeling, the most common adverse reactions, with an incidence greater than 2%, are dizziness, somnolence, nausea, fatigue, insomnia, and dry mouth.

Less common reactions include anxiety, constipation, abdominal pain, rash, sedation, and vertigo.

In studies of the drug, appendicitis was reported among 0.2% of flibanserin-treated patients, compared with no reports of appendicitis among placebo-treated patients. The FDA has requested additional investigation of the association, if any, between flibanserin 
and appendicitis.

9. What drug interactions are notable?
As stated earlier, the concomitant use of flibanserin with alcohol or a moderate or strong CYP3A4 inhibitor can result in severe hypotension and syncope. Flibanserin also should not be prescribed for patients who use other CNS depressants such as diphenhydramine, opioids, benzodiazepines, and hypnotic agents.

Some examples of strong CYP3A4 inhibitors are ketoconazole, itraconazole, posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin, and conivaptan.

Moderate CYP3A4 inhibitors include amprenavir, atazanavir, ciprofloxacin, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, and grapefruit juice.

In addition, the concomitant use of flibanserin with multiple weak CYP3A4 inhibitors—which include herbal supplements such as ginkgo and resveratrol and nonprescription drugs such as cimetidine—also may increase the risks of hypotension and syncope.

The concomitant use of flibanserin with digoxin increases the digoxin concentration and may lead to toxicity.

10. Is the drug safe in pregnancy 
and lactation?
There are currently no data on the use of flibanserin in human pregnancy. In animals, fetal toxicity occurred only in the presence of significant maternal toxicity. Adverse effects included decreased fetal weight, structural anomalies, and increases in fetal loss when exposure exceeded 15 times the recommended human dosage.

As for the advisability of using flibanserin during lactation, it is unknown whether the drug is excreted in human milk, whether it might have adverse effects in the breastfed infant, or whether it affects milk production. Package labeling states: “Because of the potential for serious adverse reactions, including sedation in a breastfed infant, breastfeeding is not recommended during treatment with [flibanserin].”¹

11. When should the drug 
be discontinued?
If there is no improvement in sexual desire after an 8-week trial of flibanserin, the drug should be 
discontinued.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

It was a long road to approval by the US Food and Drug Administration (FDA), but flibanserin (Addyi) got the nod on 
August 18, 2015. Its New Drug Application (NDA) originally was filed October 27, 2009. The drug launched October 17, 2015.

Although there has been a lot of fanfare about approval of this drug, most of the coverage has focused on its status as the “first female Viagra”—a less than accurate depiction. For a more realistic and practical assessment of the drug, OBG Management turned to Michael Krychman, MD, executive director of the Southern California Center for Sexual Health and Survivorship Medicine in Newport Beach, to determine the types of information clinicians need to know to begin prescribing flibanserin. This article highlights 11 questions (and answers) to help you get started.

1. How did the FDA arrive 
at its approval?
In 2012, the agency determined that female sexual dysfunction was one of 20 disease areas that warranted focused attention. In October 2014, as part of its intensified look at female sexual dysfunction, the FDA convened a 2-day meeting “to advance our understanding,” reports Andrea Fischer, FDA press officer.

“During the first day of the meeting, the FDA solicited patients’ perspectives on their condition and its impact on daily life. While this meeting did not focus on flibanserin, it provided an opportunity for the FDA to hear directly from patients about the impact of their condition,” Ms. Fischer says. During the second day of the meeting, the FDA “discussed scientific issues and challenges with experts in sexual medicine.”

As a result, by the time of the FDA’s 
June 4, 2015 Advisory Committee meeting on the flibanserin NDA, FDA physician-scientists were well versed in many nuances of female sexual function. That meeting included an open public hearing “that provided an opportunity for members of the public, including patients, to provide input specifically on the flibanserin application,” Ms. Fischer notes.

Nuances of the deliberations
“The FDA’s regulatory decision making on any drug product is a science-based process that carefully weighs each drug in terms of its risks and benefits to the patient population for which the drug would be indicated,” says Ms. Fischer.

The challenge in the case of flibanserin was determining whether the drug provides “clinically meaningful” improvements in sexual activity and desire.

“For many conditions and diseases, what constitutes ‘clinically meaningful’ is well known and accepted,” Ms. Fischer notes, “such as when something is cured or a severe symptom that is life-altering resolves completely. For others, this is not the case. For example, a condition that has a wide range of degree of severity can offer challenges in assessing what constitutes a clinically meaningful treatment effect. Ascertaining this requires a comprehensive knowledge of the disease, affected patient population, management strategies and the drug in question, as well as an ability to look at the clinical trial data taking this all into account.”

“In clinical trials, an important method for assessing the impact of a treatment on a patient’s symptoms, mental state, or functional status is through direct self-report using well developed and thoughtfully integrated patient-reported outcome (PRO) assessments,” Ms. Fischer says. “PROs can provide valuable information on the patient perspective when determining whether benefits outweigh risks, and they also are used to support medical product labeling claims, which are a key source of information for both health care providers and patients. PROs have been and continue to be a high priority as part of FDA’s commitment to advance patient-focused drug development, and we fully expect this to continue. The clinical trials in the flibanserin NDA all utilized PRO assessments.”

Those assessments found that patients taking flibanserin had a significant increase in “sexually satisfying events.” Three 24-week randomized controlled trials explored this endpoint for flibanserin (studies 1–3).

As for improvements in desire, the first 
2 trials utilized an e-diary to assess this aspect of sexual function, while the 3rd trial utilized the Female Sexual Function Index (FSFI).

Although the e-diary reflected no statistically significant improvement in desire in the first 2 trials, the FSFI did find significant improvement in the 3rd trial. In addition, when the FSFI was considered across all 3 trials, results in the desire domain were consistent. (The FSFI was used as a secondary tool in the first 2 trials.)

In addition, sexual distress, as measured by the Female Sexual Distress Scale (FSDS), was decreased in the trials with use of flibanserin, notes Dr. Krychman. The Advisory 
Committee determined that these findings were sufficient to demonstrate clinically meaningful improvements with use of the drug.

Although the drug was approved by the FDA, the agency was sufficiently concerned about some of its potential risks (see questions 4 and 5) that it implemented rigorous mitigation strategies (see question 7). Additional investigations were requested by the agency, including drug-drug interaction, alcohol challenge, and driving studies.

2. What are the indications?
Flibanserin is intended for use in premenopausal women who have acquired, generalized hypoactive sexual desire disorder (HSDD). That diagnosis no longer is included in the 5th edition of the Diagnostic and 
Statistical Manual of Mental Disorders but is described in drug package labeling as “low sexual desire that causes marked distress or interpersonal difficulty and is not due to:

Although the drug has been tested in both premenopausal and postmenopausal women, it was approved for use only in premenopausal women. Also note inclusion of the term “acquired” before the diagnosis of HSDD, indicating that the drug is inappropriate for women who have never experienced a period of normal sexual desire.

3. How is HSDD diagnosed?
One of the best screening tools is the 
Decreased Sexual Desire Screener, says 
Dr. Krychman. It is available at http://obgynalliance.com/files/fsd/DSDS_Pocketcard.pdf. This tool is a validated instrument to help clinicians identify what HSDD is and is not.

4. Does the drug carry 
any warnings?
Yes, it carries a black box warning about the risks of hypotension and syncope:

5. Are there any other risks worth noting?
The medication can increase the risks of hypotension and syncope even without concomitant use of alcohol. For example, in clinical trials, hypotension was reported in 0.2% of flibanserin-treated women versus less than 0.1% of placebo users. And syncope was reported in 0.4% of flibanserin users versus 0.2% of placebo-treated patients. Flibanserin is prescribed as a once-daily medication that is to be taken at bedtime; the risks of hypotension and syncope are increased if flibanserin is taken during waking hours.

The risk of adverse effects when flibanserin is taken with alcohol is highlighted by one case reported in package labeling: A 54-year-old postmenopausal woman died after taking flibanserin (100 mg daily at bedtime) for 14 days. This patient had a history of hypertension and hypercholesterolemia and consumed a baseline amount of 1 to 3 alcoholic beverages daily. She died of acute alcohol intoxication, with a blood alcohol concentration of 0.289 g/dL.¹ Whether this patient’s death was related to flibanserin use is unknown.¹

It is interesting to note that, in the studies of flibanserin leading up to the drug’s 
approval, alcohol use was not an exclusion, says Dr. Krychman. “Approximately 58% of women were self-described as mild to moderate drinkers. The clinical program was extremely large—more than 11,000 women were studied.”

Flibanserin is currently not approved for use in postmenopausal women, and concomitant alcohol consumption is contraindicated.

6. What is the dose?
The recommended dose is one tablet of 
100 mg daily. The drug is to be taken at 
bedtime to reduce the risks of hypotension, syncope, accidental injury, and central nervous system (CNS) depression, which can occur even in the absence of alcohol.

7. Are there any requirements for clinicians who want to prescribe the drug?
Yes. Because of the risks of hypotension, syncope, and CNS depression, the drug is subject to Risk Evaluation and Mitigation Strategies (REMS), as determined by the FDA. To prescribe the drug, providers must:

Before giving a patient her initial prescription, the provider must counsel her about the risks of hypotension and syncope and the interaction with alcohol using the Patient-Provider Agreement Form. The provider must then complete that form, provide a designated portion of it to the patient, and retain the remainder for the patient’s file.

For more information and to download the relevant forms, visit https://www.addyirems.com.

8. What are the most common 
adverse reactions to the drug?
According to package labeling, the most common adverse reactions, with an incidence greater than 2%, are dizziness, somnolence, nausea, fatigue, insomnia, and dry mouth.

Less common reactions include anxiety, constipation, abdominal pain, rash, sedation, and vertigo.

In studies of the drug, appendicitis was reported among 0.2% of flibanserin-treated patients, compared with no reports of appendicitis among placebo-treated patients. The FDA has requested additional investigation of the association, if any, between flibanserin 
and appendicitis.

9. What drug interactions are notable?
As stated earlier, the concomitant use of flibanserin with alcohol or a moderate or strong CYP3A4 inhibitor can result in severe hypotension and syncope. Flibanserin also should not be prescribed for patients who use other CNS depressants such as diphenhydramine, opioids, benzodiazepines, and hypnotic agents.

Some examples of strong CYP3A4 inhibitors are ketoconazole, itraconazole, posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin, and conivaptan.

Moderate CYP3A4 inhibitors include amprenavir, atazanavir, ciprofloxacin, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, and grapefruit juice.

In addition, the concomitant use of flibanserin with multiple weak CYP3A4 inhibitors—which include herbal supplements such as ginkgo and resveratrol and nonprescription drugs such as cimetidine—also may increase the risks of hypotension and syncope.

The concomitant use of flibanserin with digoxin increases the digoxin concentration and may lead to toxicity.

10. Is the drug safe in pregnancy 
and lactation?
There are currently no data on the use of flibanserin in human pregnancy. In animals, fetal toxicity occurred only in the presence of significant maternal toxicity. Adverse effects included decreased fetal weight, structural anomalies, and increases in fetal loss when exposure exceeded 15 times the recommended human dosage.

As for the advisability of using flibanserin during lactation, it is unknown whether the drug is excreted in human milk, whether it might have adverse effects in the breastfed infant, or whether it affects milk production. Package labeling states: “Because of the potential for serious adverse reactions, including sedation in a breastfed infant, breastfeeding is not recommended during treatment with [flibanserin].”¹

11. When should the drug 
be discontinued?
If there is no improvement in sexual desire after an 8-week trial of flibanserin, the drug should be 
discontinued.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Signs of chorioamnionitis ignored? $3.5M settlement
At 31 weeks’ gestation, a mother at risk for preterm labor was admitted to the hospital for 2 days. Examination and test results showed evidence of infection. She was given antenatal corticosteroids for fetal lung development in case of premature delivery. At discharge, bed rest was ordered and she complied. At 32 weeks’ gestation, she returned to the hospital with worsening symptoms, was prescribed antibiotics to treat a urinary tract infection, and was discharged. She went to the hospital a third time at almost 33 weeks’ gestation, experiencing contractions and leaking fluid. She was admitted with a plan to deliver the baby if any signs or symptoms of intra-amniotic infection (clinical chorioamnionitis) were present. Four days later, a cesarean delivery was ordered due to fetal tachycardia and decreased fetal heart rate. Imaging results performed in the neonatal intensive care unit showed that the baby received a brain injury. The child has physical and mental impairments including cerebral palsy, cortical blindness, and epilepsy.

Parents’ claim Hospital health care providers failed to communicate with each other or to obtain records from prior admissions, although the mother told them that she had been to the hospital twice within the past 2 weeks. Medical records from all 3 admissions showed clear signs and symptoms of a vaginal/cervical infection that had progressed to clinical chorioamnionitis 2 days before delivery. Examination of the placenta by a pathologist confirmed that the infection had spread to the umbilical cord, injuring the child.

Defendant’s defense The standard of care was met. There was no indication that an earlier delivery was needed.

Verdict A $3.5 million Michigan settlement was reached by the hospital during the trial.

Surgical approach questioned
A woman went to her ObGyn for tubal ligation and ventral hernia repair. The patient was concerned about infection and scarring. She agreed to a laparoscopic procedure, knowing that the procedure might have to be altered to laparotomy.

Patient’s claim The patient consented to laparoscopic surgery. However, surgery did not begin as laparoscopy but as an open procedure. The patient has a 6-inch scar on her abdomen. She accused both the ObGyn and the hospital of lack of informed consent for laparotomy.

Defendant’s defense The hospital claimed that their nurses’ role was to read the consent form signed by the patient in the ObGyn’s office. The ObGyn claimed that the patient signed a general consent form that permitted him to do what was reasonable. He had determined after surgery began that a laparoscopic procedure would have been more dangerous.

Verdict A $150,000 Louisiana verdict was returned against the ObGyn; the hospital was acquitted.

Macrosomic baby and mother both injured during delivery
Delivery of a mother’s fourth child was managed by a hospital-employed family physician (FP). Shoulder dystocia was encountered, and the FP made a 4th-degree extension of the episiotomy. The baby weighed 10 lb 14 oz at birth. The mother has fecal and urinary incontinence and pain as a result of the large episiotomy. The child has a right-sided brachial plexus injury.

Parents’ claim Failure to perform cesarean delivery caused injury to the mother and child. The FP should have recognized from the mother’s history of delivering 3 macrosomic babies and the progress of this pregnancy, that the baby was large.

Defendant’s defense The case was settled during trial.

Verdict A $1.5 million Minnesota settlement was reached that included $1.2 million for the child and $300,000 for the mother.

Surgical table folds during hysterectomy: $5.3M verdict
While a woman was undergoing a hysterectomy, the surgical table she was lying on folded up into a “U” position, causing the inserted speculum to tear the patient from vagina to rectum. The fall also caused a back injury usually attributed to falls from great distances. The patient has permanent pain, recurring diarrhea, and depression as a result of the injuries.

Patient’s claim The injuries occurred because of the defendants’ failure to read, understand, and follow the warning labels on the surgical table.

Defendant’s defense The case was settled before trial.

Verdict A $5.3 million settlement was reached with the hospital.

Signs of chorioamnionitis ignored? $3.5M settlement
At 31 weeks’ gestation, a mother at risk for preterm labor was admitted to the hospital for 2 days. Examination and test results showed evidence of infection. She was given antenatal corticosteroids for fetal lung development in case of premature delivery. At discharge, bed rest was ordered and she complied. At 32 weeks’ gestation, she returned to the hospital with worsening symptoms, was prescribed antibiotics to treat a urinary tract infection, and was discharged. She went to the hospital a third time at almost 33 weeks’ gestation, experiencing contractions and leaking fluid. She was admitted with a plan to deliver the baby if any signs or symptoms of intra-amniotic infection (clinical chorioamnionitis) were present. Four days later, a cesarean delivery was ordered due to fetal tachycardia and decreased fetal heart rate. Imaging results performed in the neonatal intensive care unit showed that the baby received a brain injury. The child has physical and mental impairments including cerebral palsy, cortical blindness, and epilepsy.

Parents’ claim Hospital health care providers failed to communicate with each other or to obtain records from prior admissions, although the mother told them that she had been to the hospital twice within the past 2 weeks. Medical records from all 3 admissions showed clear signs and symptoms of a vaginal/cervical infection that had progressed to clinical chorioamnionitis 2 days before delivery. Examination of the placenta by a pathologist confirmed that the infection had spread to the umbilical cord, injuring the child.

Defendant’s defense The standard of care was met. There was no indication that an earlier delivery was needed.

Verdict A $3.5 million Michigan settlement was reached by the hospital during the trial.

Surgical approach questioned
A woman went to her ObGyn for tubal ligation and ventral hernia repair. The patient was concerned about infection and scarring. She agreed to a laparoscopic procedure, knowing that the procedure might have to be altered to laparotomy.

Patient’s claim The patient consented to laparoscopic surgery. However, surgery did not begin as laparoscopy but as an open procedure. The patient has a 6-inch scar on her abdomen. She accused both the ObGyn and the hospital of lack of informed consent for laparotomy.

Defendant’s defense The hospital claimed that their nurses’ role was to read the consent form signed by the patient in the ObGyn’s office. The ObGyn claimed that the patient signed a general consent form that permitted him to do what was reasonable. He had determined after surgery began that a laparoscopic procedure would have been more dangerous.

Verdict A $150,000 Louisiana verdict was returned against the ObGyn; the hospital was acquitted.

Macrosomic baby and mother both injured during delivery
Delivery of a mother’s fourth child was managed by a hospital-employed family physician (FP). Shoulder dystocia was encountered, and the FP made a 4th-degree extension of the episiotomy. The baby weighed 10 lb 14 oz at birth. The mother has fecal and urinary incontinence and pain as a result of the large episiotomy. The child has a right-sided brachial plexus injury.

Parents’ claim Failure to perform cesarean delivery caused injury to the mother and child. The FP should have recognized from the mother’s history of delivering 3 macrosomic babies and the progress of this pregnancy, that the baby was large.

Defendant’s defense The case was settled during trial.

Verdict A $1.5 million Minnesota settlement was reached that included $1.2 million for the child and $300,000 for the mother.

Surgical table folds during hysterectomy: $5.3M verdict
While a woman was undergoing a hysterectomy, the surgical table she was lying on folded up into a “U” position, causing the inserted speculum to tear the patient from vagina to rectum. The fall also caused a back injury usually attributed to falls from great distances. The patient has permanent pain, recurring diarrhea, and depression as a result of the injuries.

Patient’s claim The injuries occurred because of the defendants’ failure to read, understand, and follow the warning labels on the surgical table.

Defendant’s defense The case was settled before trial.

Verdict A $5.3 million settlement was reached with the hospital.

Signs of chorioamnionitis ignored? $3.5M settlement
At 31 weeks’ gestation, a mother at risk for preterm labor was admitted to the hospital for 2 days. Examination and test results showed evidence of infection. She was given antenatal corticosteroids for fetal lung development in case of premature delivery. At discharge, bed rest was ordered and she complied. At 32 weeks’ gestation, she returned to the hospital with worsening symptoms, was prescribed antibiotics to treat a urinary tract infection, and was discharged. She went to the hospital a third time at almost 33 weeks’ gestation, experiencing contractions and leaking fluid. She was admitted with a plan to deliver the baby if any signs or symptoms of intra-amniotic infection (clinical chorioamnionitis) were present. Four days later, a cesarean delivery was ordered due to fetal tachycardia and decreased fetal heart rate. Imaging results performed in the neonatal intensive care unit showed that the baby received a brain injury. The child has physical and mental impairments including cerebral palsy, cortical blindness, and epilepsy.

Parents’ claim Hospital health care providers failed to communicate with each other or to obtain records from prior admissions, although the mother told them that she had been to the hospital twice within the past 2 weeks. Medical records from all 3 admissions showed clear signs and symptoms of a vaginal/cervical infection that had progressed to clinical chorioamnionitis 2 days before delivery. Examination of the placenta by a pathologist confirmed that the infection had spread to the umbilical cord, injuring the child.

Defendant’s defense The standard of care was met. There was no indication that an earlier delivery was needed.

Verdict A $3.5 million Michigan settlement was reached by the hospital during the trial.

Surgical approach questioned
A woman went to her ObGyn for tubal ligation and ventral hernia repair. The patient was concerned about infection and scarring. She agreed to a laparoscopic procedure, knowing that the procedure might have to be altered to laparotomy.

Patient’s claim The patient consented to laparoscopic surgery. However, surgery did not begin as laparoscopy but as an open procedure. The patient has a 6-inch scar on her abdomen. She accused both the ObGyn and the hospital of lack of informed consent for laparotomy.

Defendant’s defense The hospital claimed that their nurses’ role was to read the consent form signed by the patient in the ObGyn’s office. The ObGyn claimed that the patient signed a general consent form that permitted him to do what was reasonable. He had determined after surgery began that a laparoscopic procedure would have been more dangerous.

Verdict A $150,000 Louisiana verdict was returned against the ObGyn; the hospital was acquitted.

Macrosomic baby and mother both injured during delivery
Delivery of a mother’s fourth child was managed by a hospital-employed family physician (FP). Shoulder dystocia was encountered, and the FP made a 4th-degree extension of the episiotomy. The baby weighed 10 lb 14 oz at birth. The mother has fecal and urinary incontinence and pain as a result of the large episiotomy. The child has a right-sided brachial plexus injury.

Parents’ claim Failure to perform cesarean delivery caused injury to the mother and child. The FP should have recognized from the mother’s history of delivering 3 macrosomic babies and the progress of this pregnancy, that the baby was large.

Defendant’s defense The case was settled during trial.

Verdict A $1.5 million Minnesota settlement was reached that included $1.2 million for the child and $300,000 for the mother.

Surgical table folds during hysterectomy: $5.3M verdict
While a woman was undergoing a hysterectomy, the surgical table she was lying on folded up into a “U” position, causing the inserted speculum to tear the patient from vagina to rectum. The fall also caused a back injury usually attributed to falls from great distances. The patient has permanent pain, recurring diarrhea, and depression as a result of the injuries.

Patient’s claim The injuries occurred because of the defendants’ failure to read, understand, and follow the warning labels on the surgical table.

Defendant’s defense The case was settled before trial.

Verdict A $5.3 million settlement was reached with the hospital.

Bacillus Calmette-Guérin (BCG) is the only intravesical therapy shown to be associated with decreased risk of bladder cancer progression, according to a report by the Agency for Healthcare Research and Quality (AHRQ), but the researchers cautioned that the therapy was associated with a high rate of adverse events.

The Comparative Effectiveness Review, headed by Dr. Roger Chou and based on research by the Pacific Northwest Evidence-Based Practice Center (EPC) under contract to the AHRQ, was conducted as a systematic review of trials identified via electronic databases and conducted from 1990 to 2014.

BCG was associated with a higher rate of local and systemic adverse events (granulomatous cystitis or irritative symptoms in 27%-84% of patients, macroscopic hematuria in 21%-72%, and fever in 27%-44%) when compared with no intravesical therapy, the researchers wrote. BCG was associated with decreased risk of bladder cancer progression, but no intravesical agent was associated with decreased risk of all-cause or bladder cancer mortality.

In addition, fluorescent cystoscopy was associated with decreased risk of subsequent bladder recurrence, compared with white light cystoscopy, but results were inconsistent through many of the trials identified.

Read the full report here.

mbock@frontlinemedcom.com

Bacillus Calmette-Guérin (BCG) is the only intravesical therapy shown to be associated with decreased risk of bladder cancer progression, according to a report by the Agency for Healthcare Research and Quality (AHRQ), but the researchers cautioned that the therapy was associated with a high rate of adverse events.

The Comparative Effectiveness Review, headed by Dr. Roger Chou and based on research by the Pacific Northwest Evidence-Based Practice Center (EPC) under contract to the AHRQ, was conducted as a systematic review of trials identified via electronic databases and conducted from 1990 to 2014.

BCG was associated with a higher rate of local and systemic adverse events (granulomatous cystitis or irritative symptoms in 27%-84% of patients, macroscopic hematuria in 21%-72%, and fever in 27%-44%) when compared with no intravesical therapy, the researchers wrote. BCG was associated with decreased risk of bladder cancer progression, but no intravesical agent was associated with decreased risk of all-cause or bladder cancer mortality.

In addition, fluorescent cystoscopy was associated with decreased risk of subsequent bladder recurrence, compared with white light cystoscopy, but results were inconsistent through many of the trials identified.

Read the full report here.

mbock@frontlinemedcom.com

Bacillus Calmette-Guérin (BCG) is the only intravesical therapy shown to be associated with decreased risk of bladder cancer progression, according to a report by the Agency for Healthcare Research and Quality (AHRQ), but the researchers cautioned that the therapy was associated with a high rate of adverse events.

The Comparative Effectiveness Review, headed by Dr. Roger Chou and based on research by the Pacific Northwest Evidence-Based Practice Center (EPC) under contract to the AHRQ, was conducted as a systematic review of trials identified via electronic databases and conducted from 1990 to 2014.

BCG was associated with a higher rate of local and systemic adverse events (granulomatous cystitis or irritative symptoms in 27%-84% of patients, macroscopic hematuria in 21%-72%, and fever in 27%-44%) when compared with no intravesical therapy, the researchers wrote. BCG was associated with decreased risk of bladder cancer progression, but no intravesical agent was associated with decreased risk of all-cause or bladder cancer mortality.

In addition, fluorescent cystoscopy was associated with decreased risk of subsequent bladder recurrence, compared with white light cystoscopy, but results were inconsistent through many of the trials identified.

Read the full report here.

mbock@frontlinemedcom.com