A 41-year-old woman presented with intermittent shortness of breath that worsened with exposure to cold air and cigarette smoke. She said her symptoms got better when she used albuterol, which had been prescribed after an emergency department visit during a worsening episode.

The patient was severely obese (body mass index 48 kg/m²) and had bilateral expiratory wheezes but no other significant findings. Based on the clinical presentation, we suspected she had asthma.

To establish the diagnosis and assess the severity of her condition, we questioned her further about her symptoms, and this information increased our suspicion of asthma. Is spirometry also indicated?

SPIROMETRY’S ROLE IN DIAGNOSING ASTHMA

Asthma is a chronic inflammatory condition of the airways characterized by recurrent or persistent symptoms with evidence of variable airflow obstruction or hyperresponsiveness to certain stimuli.¹ The clinical diagnosis is based on episodic symptoms of chest tightness, wheezing, shortness of breath, or cough, but we cannot reliably diagnose asthma based on symptoms alone.

Spirometry provides an objective measure of obstruction, which adds to the reliability of the diagnosis. Therefore, it should be done in all patients in whom asthma is suspected.

Spirometry provides another diagnostic measure by quantifying whether airway obstruction reverses after the patient is given a dose of a bronchodilator. Although the exact criteria for reversibility of obstruction are unclear, the American Thoracic Society defines it as an increase in the forced expiratory volume in 1 second (FEV₁) of 12% or more from baseline and an absolute increase of 200 mL or more. It can also be an increase of more than 200 mL in the forced vital capacity (FVC).^2,3

Spirometry can also be used to evaluate or rule out other causes of chronic shortness of breath and common asthma mimics.

Failure to perform spirometry can result in a false diagnosis of asthma in patients who do not have it, or in a missed diagnosis in patients who do.^4,5 Either situation often leads to inappropriate use of medications, exposure of patients to side effects, delays in appropriate diagnosis, and ongoing morbidity.

Despite the evidence in its favor, spirometry is underused. In a 2012 Canadian study, only 42.7% of 465,866 patients with newly diagnosed asthma had any spirometry testing performed within 1 year before or 2.5 years after the diagnosis.⁶ Similarly, in a 2015 US study, only 47.6% of 134,208 patients had spirometry performed within 1 year of diagnosis.⁷ Interestingly, this study found that the use of spirometry actually decreased after publication of guidelines from the National Asthma Education and Prevention Program¹ that recommended spirometry.

CASE CONTINUED

Her baseline values were normal; her FEV₁/FVC ratio was 73.67% (lower limit of normal 72.62%) and thus was not significant for airway obstruction. However, after 4 puffs of an inhaled short-acting beta agonist, her FEV₁ increased by 15% from baseline (from 1.98 L/second before to 2.25 L/second after), a clinically significant response (defined as ≥ 12% from baseline and an absolute increase of at least 200 mL^1–3). Had we not included bronchodilator testing, given the absence of underlying baseline obstruction, her shortness of breath could have been attributed to other causes, resulting in a missed asthma diagnosis.

Nevertheless, postbronchodilator measurements should not be performed in all patients with normal baseline results unless asthma is strongly suspected on clinical grounds. In one study, only 3% of 1,394 patients with normal baseline results showed improvement with a bronchodilator.⁸ In this patient population, bronchodilator testing would add both time and cost with little benefit.

Our patient’s reversibility of obstruction helped confirm the diagnosis of asthma. Absence of reversibility, however, does not rule out asthma, because spirometry results, like clinical symptoms of asthma, can vary. If clinical suspicion remains high and spirometry does not show clinically significant reversibility, then bronchoprovocation testing (most commonly with methacholine) could be done.

Although a positive methacholine challenge test can help identify asthma in patients with atypical symptoms or normal baseline test results, conditions other than asthma can also cause positive results. The sensitivity of methacholine challenge has been reported to be as high as 96%, while its specificity averages less than 80%.⁹ Given its high negative predictive value, the test can help rule out asthma, as negative results are rarely falsely negative.

Once the diagnosis of asthma is established, its severity and control need to be assessed to guide therapy. This is typically done by ascertaining how often the patient experiences asthma symptoms, how often the patient uses short-acting beta agonists (ranging from days per month to multiple times a day), and how often he or she has nighttime symptoms. The most severe symptom or most abnormal response is used to categorize asthma as intermittent or persistent, with severity ranging from mild to severe.

Symptoms are not always effective measures of asthma control, and subjective measures of symptoms often do not correlate with asthma severity, resulting in underestimation of the degree of airway obstruction.^10,11 A review of 500 patients with an established asthma diagnosis found that in 110 patients with self-reported control of symptoms that included use of short-acting beta agonists no more than once per day, no night awakenings in the past week, and no missed school or work in the past 3 months, only 61 (55%) had an FEV₁ above 80% of predicted.¹² Further, neither the FEV₁ nor FEV₁/FVC ratio was shown to have a direct relationship with subjective measures of disease severity or control.

These observations highlight the need to use the objective findings from spirometry to assess asthma control and severity. Relying on the clinical symptoms alone likely underestimates the severity of asthma, especially in patients who are “poor perceivers” of symptoms. This can lead to undertreatment or an inappropriate step-down in therapy.

Current guidelines recommend repeating spirometry once therapy has brought the disease under control to establish a true baseline of airway function.^1–3 Spirometry should be repeated again during any prolonged loss of asthma control and at 1- to 2-year intervals in patients with well-controlled disease as a means to monitor disease progression by measuring changes in airway function over time.

ROLE IN PREDICTING EXACERBATIONS

Current questionnaire-based assessments of breathing symptoms focus on disease severity and control, not on the risk of exacerbation. Although it may seem intuitive that patients who have the most severe disease are at highest risk of exacerbations, many patients with “mild” disease and “good” control experience exacerbations that require expensive emergency department visits. Nearly half of all the money spent on direct medical care for asthma is for urgent outpatient clinic and emergency department visits and hospitalizations.¹³

Using the FEV₁, either by itself or in combination with other diagnostic tools such as questionnaires, has been shown to be superior to the clinical history alone in identifying patients at high risk of acute exacerbations.^14,15 In addition to improving patient care and quality of life, spirometry could substantially reduce costs of care.

BOTTOM LINE

Although asthma remains a clinical diagnosis based on episodic symptoms consistent with airflow obstruction, symptoms alone cannot reliably be used to diagnose the disease or assess its severity and control.

Spirometry, including FEV₁ and FVC, is an important objective measure to help with the diagnosis and should be done in all patients in whom asthma is suspected, both at the time of diagnosis and at intervals to assess disease progression. Spirometry also provides data to help assess the severity of asthma, which often does not correlate with clinical perception of symptoms, and it can be a predictive tool to identify patients at high risk for exacerbation, a common cause of emergency room visits and hospitalizations.

Some patients perceive spirometry as cumbersome and do not want to do it or cannot do it—spirometry takes quite a bit of effort and coordination while following directions. Also, it is not always easy to do, as patients with severe obstruction have a hard time maximally exhaling. Nevertheless, testing is safe, with few risks or adverse outcomes and can be easily performed in primary care settings and subspecialty clinics.

A 41-year-old woman presented with intermittent shortness of breath that worsened with exposure to cold air and cigarette smoke. She said her symptoms got better when she used albuterol, which had been prescribed after an emergency department visit during a worsening episode.

The patient was severely obese (body mass index 48 kg/m²) and had bilateral expiratory wheezes but no other significant findings. Based on the clinical presentation, we suspected she had asthma.

To establish the diagnosis and assess the severity of her condition, we questioned her further about her symptoms, and this information increased our suspicion of asthma. Is spirometry also indicated?

SPIROMETRY’S ROLE IN DIAGNOSING ASTHMA

Asthma is a chronic inflammatory condition of the airways characterized by recurrent or persistent symptoms with evidence of variable airflow obstruction or hyperresponsiveness to certain stimuli.¹ The clinical diagnosis is based on episodic symptoms of chest tightness, wheezing, shortness of breath, or cough, but we cannot reliably diagnose asthma based on symptoms alone.

Spirometry provides an objective measure of obstruction, which adds to the reliability of the diagnosis. Therefore, it should be done in all patients in whom asthma is suspected.

Spirometry provides another diagnostic measure by quantifying whether airway obstruction reverses after the patient is given a dose of a bronchodilator. Although the exact criteria for reversibility of obstruction are unclear, the American Thoracic Society defines it as an increase in the forced expiratory volume in 1 second (FEV₁) of 12% or more from baseline and an absolute increase of 200 mL or more. It can also be an increase of more than 200 mL in the forced vital capacity (FVC).^2,3

Spirometry can also be used to evaluate or rule out other causes of chronic shortness of breath and common asthma mimics.

Failure to perform spirometry can result in a false diagnosis of asthma in patients who do not have it, or in a missed diagnosis in patients who do.^4,5 Either situation often leads to inappropriate use of medications, exposure of patients to side effects, delays in appropriate diagnosis, and ongoing morbidity.

Despite the evidence in its favor, spirometry is underused. In a 2012 Canadian study, only 42.7% of 465,866 patients with newly diagnosed asthma had any spirometry testing performed within 1 year before or 2.5 years after the diagnosis.⁶ Similarly, in a 2015 US study, only 47.6% of 134,208 patients had spirometry performed within 1 year of diagnosis.⁷ Interestingly, this study found that the use of spirometry actually decreased after publication of guidelines from the National Asthma Education and Prevention Program¹ that recommended spirometry.

CASE CONTINUED

Her baseline values were normal; her FEV₁/FVC ratio was 73.67% (lower limit of normal 72.62%) and thus was not significant for airway obstruction. However, after 4 puffs of an inhaled short-acting beta agonist, her FEV₁ increased by 15% from baseline (from 1.98 L/second before to 2.25 L/second after), a clinically significant response (defined as ≥ 12% from baseline and an absolute increase of at least 200 mL^1–3). Had we not included bronchodilator testing, given the absence of underlying baseline obstruction, her shortness of breath could have been attributed to other causes, resulting in a missed asthma diagnosis.

Nevertheless, postbronchodilator measurements should not be performed in all patients with normal baseline results unless asthma is strongly suspected on clinical grounds. In one study, only 3% of 1,394 patients with normal baseline results showed improvement with a bronchodilator.⁸ In this patient population, bronchodilator testing would add both time and cost with little benefit.

Our patient’s reversibility of obstruction helped confirm the diagnosis of asthma. Absence of reversibility, however, does not rule out asthma, because spirometry results, like clinical symptoms of asthma, can vary. If clinical suspicion remains high and spirometry does not show clinically significant reversibility, then bronchoprovocation testing (most commonly with methacholine) could be done.

Although a positive methacholine challenge test can help identify asthma in patients with atypical symptoms or normal baseline test results, conditions other than asthma can also cause positive results. The sensitivity of methacholine challenge has been reported to be as high as 96%, while its specificity averages less than 80%.⁹ Given its high negative predictive value, the test can help rule out asthma, as negative results are rarely falsely negative.

Once the diagnosis of asthma is established, its severity and control need to be assessed to guide therapy. This is typically done by ascertaining how often the patient experiences asthma symptoms, how often the patient uses short-acting beta agonists (ranging from days per month to multiple times a day), and how often he or she has nighttime symptoms. The most severe symptom or most abnormal response is used to categorize asthma as intermittent or persistent, with severity ranging from mild to severe.

Symptoms are not always effective measures of asthma control, and subjective measures of symptoms often do not correlate with asthma severity, resulting in underestimation of the degree of airway obstruction.^10,11 A review of 500 patients with an established asthma diagnosis found that in 110 patients with self-reported control of symptoms that included use of short-acting beta agonists no more than once per day, no night awakenings in the past week, and no missed school or work in the past 3 months, only 61 (55%) had an FEV₁ above 80% of predicted.¹² Further, neither the FEV₁ nor FEV₁/FVC ratio was shown to have a direct relationship with subjective measures of disease severity or control.

These observations highlight the need to use the objective findings from spirometry to assess asthma control and severity. Relying on the clinical symptoms alone likely underestimates the severity of asthma, especially in patients who are “poor perceivers” of symptoms. This can lead to undertreatment or an inappropriate step-down in therapy.

Current guidelines recommend repeating spirometry once therapy has brought the disease under control to establish a true baseline of airway function.^1–3 Spirometry should be repeated again during any prolonged loss of asthma control and at 1- to 2-year intervals in patients with well-controlled disease as a means to monitor disease progression by measuring changes in airway function over time.

ROLE IN PREDICTING EXACERBATIONS

Current questionnaire-based assessments of breathing symptoms focus on disease severity and control, not on the risk of exacerbation. Although it may seem intuitive that patients who have the most severe disease are at highest risk of exacerbations, many patients with “mild” disease and “good” control experience exacerbations that require expensive emergency department visits. Nearly half of all the money spent on direct medical care for asthma is for urgent outpatient clinic and emergency department visits and hospitalizations.¹³

Using the FEV₁, either by itself or in combination with other diagnostic tools such as questionnaires, has been shown to be superior to the clinical history alone in identifying patients at high risk of acute exacerbations.^14,15 In addition to improving patient care and quality of life, spirometry could substantially reduce costs of care.

BOTTOM LINE

Although asthma remains a clinical diagnosis based on episodic symptoms consistent with airflow obstruction, symptoms alone cannot reliably be used to diagnose the disease or assess its severity and control.

Spirometry, including FEV₁ and FVC, is an important objective measure to help with the diagnosis and should be done in all patients in whom asthma is suspected, both at the time of diagnosis and at intervals to assess disease progression. Spirometry also provides data to help assess the severity of asthma, which often does not correlate with clinical perception of symptoms, and it can be a predictive tool to identify patients at high risk for exacerbation, a common cause of emergency room visits and hospitalizations.

Some patients perceive spirometry as cumbersome and do not want to do it or cannot do it—spirometry takes quite a bit of effort and coordination while following directions. Also, it is not always easy to do, as patients with severe obstruction have a hard time maximally exhaling. Nevertheless, testing is safe, with few risks or adverse outcomes and can be easily performed in primary care settings and subspecialty clinics.

A 41-year-old woman presented with intermittent shortness of breath that worsened with exposure to cold air and cigarette smoke. She said her symptoms got better when she used albuterol, which had been prescribed after an emergency department visit during a worsening episode.

The patient was severely obese (body mass index 48 kg/m²) and had bilateral expiratory wheezes but no other significant findings. Based on the clinical presentation, we suspected she had asthma.

To establish the diagnosis and assess the severity of her condition, we questioned her further about her symptoms, and this information increased our suspicion of asthma. Is spirometry also indicated?

SPIROMETRY’S ROLE IN DIAGNOSING ASTHMA

Asthma is a chronic inflammatory condition of the airways characterized by recurrent or persistent symptoms with evidence of variable airflow obstruction or hyperresponsiveness to certain stimuli.¹ The clinical diagnosis is based on episodic symptoms of chest tightness, wheezing, shortness of breath, or cough, but we cannot reliably diagnose asthma based on symptoms alone.

Spirometry provides an objective measure of obstruction, which adds to the reliability of the diagnosis. Therefore, it should be done in all patients in whom asthma is suspected.

Spirometry provides another diagnostic measure by quantifying whether airway obstruction reverses after the patient is given a dose of a bronchodilator. Although the exact criteria for reversibility of obstruction are unclear, the American Thoracic Society defines it as an increase in the forced expiratory volume in 1 second (FEV₁) of 12% or more from baseline and an absolute increase of 200 mL or more. It can also be an increase of more than 200 mL in the forced vital capacity (FVC).^2,3

Spirometry can also be used to evaluate or rule out other causes of chronic shortness of breath and common asthma mimics.

Failure to perform spirometry can result in a false diagnosis of asthma in patients who do not have it, or in a missed diagnosis in patients who do.^4,5 Either situation often leads to inappropriate use of medications, exposure of patients to side effects, delays in appropriate diagnosis, and ongoing morbidity.

Despite the evidence in its favor, spirometry is underused. In a 2012 Canadian study, only 42.7% of 465,866 patients with newly diagnosed asthma had any spirometry testing performed within 1 year before or 2.5 years after the diagnosis.⁶ Similarly, in a 2015 US study, only 47.6% of 134,208 patients had spirometry performed within 1 year of diagnosis.⁷ Interestingly, this study found that the use of spirometry actually decreased after publication of guidelines from the National Asthma Education and Prevention Program¹ that recommended spirometry.

CASE CONTINUED

Her baseline values were normal; her FEV₁/FVC ratio was 73.67% (lower limit of normal 72.62%) and thus was not significant for airway obstruction. However, after 4 puffs of an inhaled short-acting beta agonist, her FEV₁ increased by 15% from baseline (from 1.98 L/second before to 2.25 L/second after), a clinically significant response (defined as ≥ 12% from baseline and an absolute increase of at least 200 mL^1–3). Had we not included bronchodilator testing, given the absence of underlying baseline obstruction, her shortness of breath could have been attributed to other causes, resulting in a missed asthma diagnosis.

Nevertheless, postbronchodilator measurements should not be performed in all patients with normal baseline results unless asthma is strongly suspected on clinical grounds. In one study, only 3% of 1,394 patients with normal baseline results showed improvement with a bronchodilator.⁸ In this patient population, bronchodilator testing would add both time and cost with little benefit.

Our patient’s reversibility of obstruction helped confirm the diagnosis of asthma. Absence of reversibility, however, does not rule out asthma, because spirometry results, like clinical symptoms of asthma, can vary. If clinical suspicion remains high and spirometry does not show clinically significant reversibility, then bronchoprovocation testing (most commonly with methacholine) could be done.

Although a positive methacholine challenge test can help identify asthma in patients with atypical symptoms or normal baseline test results, conditions other than asthma can also cause positive results. The sensitivity of methacholine challenge has been reported to be as high as 96%, while its specificity averages less than 80%.⁹ Given its high negative predictive value, the test can help rule out asthma, as negative results are rarely falsely negative.

Once the diagnosis of asthma is established, its severity and control need to be assessed to guide therapy. This is typically done by ascertaining how often the patient experiences asthma symptoms, how often the patient uses short-acting beta agonists (ranging from days per month to multiple times a day), and how often he or she has nighttime symptoms. The most severe symptom or most abnormal response is used to categorize asthma as intermittent or persistent, with severity ranging from mild to severe.

Symptoms are not always effective measures of asthma control, and subjective measures of symptoms often do not correlate with asthma severity, resulting in underestimation of the degree of airway obstruction.^10,11 A review of 500 patients with an established asthma diagnosis found that in 110 patients with self-reported control of symptoms that included use of short-acting beta agonists no more than once per day, no night awakenings in the past week, and no missed school or work in the past 3 months, only 61 (55%) had an FEV₁ above 80% of predicted.¹² Further, neither the FEV₁ nor FEV₁/FVC ratio was shown to have a direct relationship with subjective measures of disease severity or control.

These observations highlight the need to use the objective findings from spirometry to assess asthma control and severity. Relying on the clinical symptoms alone likely underestimates the severity of asthma, especially in patients who are “poor perceivers” of symptoms. This can lead to undertreatment or an inappropriate step-down in therapy.

Current guidelines recommend repeating spirometry once therapy has brought the disease under control to establish a true baseline of airway function.^1–3 Spirometry should be repeated again during any prolonged loss of asthma control and at 1- to 2-year intervals in patients with well-controlled disease as a means to monitor disease progression by measuring changes in airway function over time.

ROLE IN PREDICTING EXACERBATIONS

Current questionnaire-based assessments of breathing symptoms focus on disease severity and control, not on the risk of exacerbation. Although it may seem intuitive that patients who have the most severe disease are at highest risk of exacerbations, many patients with “mild” disease and “good” control experience exacerbations that require expensive emergency department visits. Nearly half of all the money spent on direct medical care for asthma is for urgent outpatient clinic and emergency department visits and hospitalizations.¹³

Using the FEV₁, either by itself or in combination with other diagnostic tools such as questionnaires, has been shown to be superior to the clinical history alone in identifying patients at high risk of acute exacerbations.^14,15 In addition to improving patient care and quality of life, spirometry could substantially reduce costs of care.

BOTTOM LINE

Although asthma remains a clinical diagnosis based on episodic symptoms consistent with airflow obstruction, symptoms alone cannot reliably be used to diagnose the disease or assess its severity and control.

Spirometry, including FEV₁ and FVC, is an important objective measure to help with the diagnosis and should be done in all patients in whom asthma is suspected, both at the time of diagnosis and at intervals to assess disease progression. Spirometry also provides data to help assess the severity of asthma, which often does not correlate with clinical perception of symptoms, and it can be a predictive tool to identify patients at high risk for exacerbation, a common cause of emergency room visits and hospitalizations.

Some patients perceive spirometry as cumbersome and do not want to do it or cannot do it—spirometry takes quite a bit of effort and coordination while following directions. Also, it is not always easy to do, as patients with severe obstruction have a hard time maximally exhaling. Nevertheless, testing is safe, with few risks or adverse outcomes and can be easily performed in primary care settings and subspecialty clinics.

Delirium is common in hospitalized patients and contributes to healthcare costs and poor patient outcomes, including death. Its diagnosis and management remain clinically challenging. Although consensus panel guidelines recommend antipsychotic medications to treat delirium when conservative measures fail, few head-to-head trials have been done to tell us which antipsychotic drug to select, and antipsychotic use poses risks in the elderly.

Here, we review the risks and benefits of using antipsychotic drugs to manage delirium and describe an approach to selecting and using 5 commonly used antipsychotics.

SCOPE OF THE PROBLEM

Delirium is common and serious, affecting 11% to 42% of patients hospitalized on general medical wards.¹ The burden to the public and individual patient is extremely high. Delirium has been found to result in an additional $16,303 to $64,421 per delirious patient per year, with a subsequent total 1-year health-attributable cost between $38 billion and $152 billion in the United States.² Furthermore, many patients who become delirious in the hospital lose their independence and are placed in long-term care facilities.³

Although delirium was originally thought to be a time-limited neurocognitive disorder, recent evidence shows that it persists much longer⁴ and that some patients never return to their previous level of function, suggesting that a single episode of delirium can significantly alter the course of an underlying dementia with the dramatic initiation of cognitive decline.³ Most alarmingly, delirium is associated with an increased rate of death.¹  

DSM-5 DEFINITION

According to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5),⁵ delirium is a neurocognitive disorder characterized by the acute onset of disturbance in attention, awareness, and cognition that fluctuates in severity throughout the day and is the direct physiologic consequence of another medical condition. The cognitive impairment seen in delirium is typically global and can affect memory, orientation, language, visuospatial ability, and perception. Other prominent features include psychomotor disturbance, sleep-cycle derangement, and emotional lability.

The pathogenesis of delirium is not clearly delineated but may relate to cholinergic deficiency and dopaminergic excess.

THE FIRST STEPS: NONPHARMACOLOGIC MANAGEMENT

Inouye³ outlined a general 3-part approach to managing delirium:

Identify and address predisposing factors. All patients found to have an acute change in mental status should be evaluated for the underlying cause, with special attention to the most common causes, ie, infection, metabolic derangement, and substance intoxication and withdrawal. A thorough medication reconciliation should also be done to identify medications with psychoactive or anticholinergic effects.

Provide supportive care, eg, addressing volume and nutritional status, mobilizing the patient early, and giving prophylaxis against deep venous thrombosis.

Manage symptoms. Behavioral strategies should be instituted in every delirious patient and should include frequent reorientation, use of observers, encouragement of family involvement, avoidance of physical restraints and Foley catheters, use of vision and hearing aids, and normalizing the sleep-wake cycle.

ANTIPSYCHOTICS: ARE THEY SAFE AND EFFECTIVE?

The US Food and Drug Administration (FDA) has not approved any medications for delirium. However, multiple consensus statements, including those by the American Psychiatric Association,⁶ the Canadian Coalition for Seniors’ Mental Health,⁷ and the UK National Institute for Health and Care Excellence,⁸ advocate for psychopharmacologic management of delirium symptoms in the following situations:

• The patient is in significant distress from his or her symptoms
• The patient poses a safety risk to self or others
• The patient is impeding essential aspects of his or her medical care.

Guidelines from these organizations recommend antipsychotic medications as the first-line drugs for managing delirium symptoms not caused by substance withdrawal. Nevertheless, the use of antipsychotics in the management of delirium remains controversial. While a number of studies suggest these drugs are beneficial,^9–11 others do not.¹² These consensus panels advocate for the judicious use of antipsychotics, limited to the specific situations outlined above.

The use of antipsychotics in elderly and medically complex patients poses risks. One of the most significant safety concerns is increased risk of death due to adverse cardiac events caused by prolongation of the QT interval.

Antipsychotics, QT prolongation, and torsades de pointes

Most antipsychotics have the potential to prolong the time of ventricular depolarization and repolarization and the QT interval to some extent, which can lead to torsades de pointes.¹³ Other risk factors for prolonged QT interval and torsades de pointes include:

• Long QT syndrome (a genetic arrhythmia)
• Female sex
• Old age
• Electrolyte abnormalities (hypokalemia, hypocalcemia, hypomagnesemia)
• Preexisting heart conditions such as bradycardia, left ventricular dysfunction, heart failure, mitral valve prolapse, and previous myocardial infarction
• Medical conditions that cause electrolyte derangements
• Medications, including antiarrhythmics, antibiotics (macrolides, quinolones), antifungals, antimalarials, antiemetics, some opioids (methadone), and most antipsychotics.

Haloperidol. Postmarketing analysis in 2007 found 73 cases of haloperidol-related torsades de pointes. However, many of these were confounded by other QT-prolonging medications and medical conditions.¹⁴

The QT-prolonging effect of haloperidol administered orally or intramuscularly is actually quite small. The equivalent oral dose of 15 mg of haloperidol (assuming 50% bioavailability) given orally or intramuscularly increases the corrected QT interval (QTc) by only 7 to 8 milliseconds. But intravenous haloperidol can cause much more significant QT prolongation: 8 of the 11 reported cases of fatal torsades de pointes occurred when haloperidol was given intravenously.¹⁴ Therefore, the FDA recommends cardiac monitoring for all patients receiving intravenous haloperidol.

Oral olanzapine, risperidone, and quetiapine prolong the QT interval approximately as much as oral haloperidol.

Aripiprazole has not been associated with significant QT prolongation.¹³

The FDA has issued multiple warnings for prescribing antipsychotic medications in the elderly. In 2003, it warned prescribers of increased cerebrovascular adverse events, including stroke, in elderly patients with dementia who were treated with an atypical antipsychotic (risperidone, olanzapine, or aripiprazole) vs placebo.¹⁵

Atypical antipsychotics and risk of death

In 2005, the FDA issued a black-box warning about increased all-cause mortality risk in patients with dementia treated with atypical antipsychotics for behavioral disturbance (relative risk 1.6–1.7).¹⁶

This warning was likely based on a meta-analysis by Schneider et al¹⁷ of trials in which patients with dementia were randomized to receive either an atypical antipsychotic or placebo. The death rate was 3.5% in patients treated with an atypical antipsychotic vs 2.3% in patients treated with placebo, indicating a number needed to harm of 100. The most common causes of death were cardiovascular disease and pneumonia. However, the trials in this meta-analysis included only patients who were prescribed atypical antipsychotics for ongoing management of behavioral disturbances due to dementia in either the outpatient or nursing home setting. None of the trials looked at patients who were prescribed atypical antipsychotics for a limited time in a closely monitored inpatient setting.

Effectiveness of antipsychotics

While several studies since the FDA black-box warning have shown that antipsychotics are safe, the efficacy of these drugs in delirium management remains controversial.

In a 2016 meta-analysis, Kishi et al¹⁸ found that antipsychotics were superior to placebo in terms of response rate (defined as improvement of delirium severity rating scores), with a number needed to treat of 2.

In contrast, a meta-analysis by Neufeld et al¹² found that antipsychotic use was not associated with a change in delirium duration, severity, or length of stay in the hospital or intensive care unit. However, the studies in this meta-analysis varied widely in age range, study design, drug comparison, and treatment strategy (with drugs given as both prophylaxis and treatment). Thus, the results are difficult to interpret.

Kishi et al¹⁸ found no difference in the incidence of death, extrapyramidal symptoms, akathisia, or QT prolongation between patients treated with antipsychotic drugs vs placebo.

In a prospective observational study, Hatta et al¹⁹ followed 2,453 inpatients who became delirious. Only 22 (0.9%) experienced adverse events attributable to antipsychotic use, the most common being aspiration pneumonia (0.7%), followed by cardiovascular events (0.2%). Notably, no patient died of antipsychotic-related events. In this study, the antipsychotic was stopped as soon as the delirium symptoms resolved, in most cases in 3 to 7 days.

Taken together, these studies indicate that despite the risk of QT prolongation with antipsychotic use and increased rates of morbidity with antipsychotic use in dementia, time-limited management of delirium with antipsychotics is effective^9–11 and safe.

SELECTING AND USING ANTIPSYCHOTICS TO TREAT DELIRIUM

Identifying a single preferred agent is difficult, since we lack enough evidence from randomized controlled trials that directly compared the various antipsychotics used in delirium management.

Both typical and atypical antipsychotics are used in clinical practice to manage delirium. The typical antipsychotic most often used is haloperidol, while the most commonly used atypical antipsychotics for delirium include olanzapine, quetiapine, risperidone, and (more recently) aripiprazole.

The American Psychiatric Association guidelines⁶ suggest using haloperidol because it is the antipsychotic that has been most studied for delirium,²⁰ and we have decades of experience with its use. Despite this, recent prospective studies have suggested that the atypical antipsychotics may be better because they have a faster onset of action and lower incidence of extrapyramidal symptoms.^18,21

Because we lack enough head-to-head trials comparing the efficacy of the 5 most commonly used antipsychotics for the management of delirium, and because the prospective trials that do exist show equal efficacy across the antipsychotics studied,²² we suggest considering the unique pharmacologic properties of each drug within the patient’s clinical context when selecting which antipsychotic to use.

Table 1^23–25 summarizes some key characteristics of the 5 most commonly used antipsychotics.

Haloperidol

Haloperidol, a typical antipsychotic, is a potent antagonist of the dopamine D2 receptor.

Haloperidol has the advantage of having the strongest evidence base for use in delirium. In addition, it is available in oral, intravenous, and intramuscular dosage forms, and it has minimal effects on vital signs, negligible anticholinergic activity, and minimal interactions with other medications.²¹

Intravenous haloperidol poses a significant risk of QT prolongation and so should be used judiciously in patients with preexisting cardiac conditions or other risk factors for QT prolongation as outlined above, and with careful cardiac monitoring. Parenteral haloperidol is approximately twice as potent as oral haloperidol.

Some evidence suggests a higher risk of acute dystonia and other extrapyramidal symptoms with haloperidol than with the atypical antipsychotics.^21,26 In contrast, a 2013 prospective study showed that low doses of haloperidol (< 3.5 mg/day) did not result in a greater frequency of extrapyramidal symptoms.²² Nevertheless, if a patient has a history of extrapyramidal symptoms, haloperidol should likely be avoided in favor of an atypical antipsychotic.

Olanzapine, quetiapine, and risperidone are atypical antipsychotics that, like haloperidol, antagonize the dopamine D2 receptor, but also have antagonist action at serotonin, histamine, and alpha-2 receptors. This multireceptor antagonism reduces the risk of extrapyramidal symptoms but increases the risk of orthostatic hypotension.

Quetiapine, in particular, imposes an unacceptably high risk of orthostatic hypotension and so is not recommended for use in delirium in the emergency department.²⁷ Additionally, quetiapine is anticholinergic, raising concerns about constipation and urinary retention.

Although the association between fall risk and antipsychotic use remains controversial,^28,29 a study found that olanzapine conferred a lower fall risk than quetiapine and risperidone.³⁰

Of these drugs, only olanzapine is available in an intramuscular dosage form. Both risperidone and olanzapine are available in dissolvable tablets; however, they are not sublingually absorbed.

Randomized controlled trials have shown that olanzapine is effective in managing cancer-related nausea, and therefore it may be useful in managing delirium in oncology patients.^31,32

Patients with Parkinson disease are exquisitely sensitive to the antidopaminergic effects of antipsychotics but are also vulnerable to delirium, so they present a unique treatment challenge. The agent of choice in patients with Parkinson disease is quetiapine, as multiple trials have shown it has no effect on the motor symptoms of Parkinson disease (reviewed by Desmarais et al in a systematic meta-analysis³³).

Aripiprazole is increasingly used to manage delirium. Its mechanism of action differs from that of the other atypical antipsychotics, as it is a partial dopamine agonist. It is available in oral, orally dissolvable, and intramuscular forms. It appears to be slightly less effective than the other atypical antipsychotics,³⁴ but it may be useful for hypoactive delirium as it is less sedating than the other agents.³⁵ Because its effect on the QT interval is negligible, it may also be favored in patients who have a high baseline QTc or other predisposing factors for torsades de pointes.

BALANCING THE RISKS

Antipsychotic drugs have been shown to be effective and generally safe. Antipsychotics do prolong the QT interval. However, other than with intravenous administration of haloperidol, the absolute effect is minimal. Although large meta-analyses have shown a higher rate of all-cause mortality in elderly outpatients with dementia who are prescribed atypical antipsychotics, an increase in death rates has not been borne out by prospective studies focusing on hospitalized patients who receive low doses of antipsychotics for a limited time.

There are no head-to-head randomized controlled trials comparing the efficacy of all of the 5 most commonly used antipsychotics. Therefore, we suggest considering the unique psychopharmacologic properties of each agent within the patient’s clinical setting, specifically taking into account the risk of cardiac arrhythmia, risk of orthostasis and falls, history of extrapyramidal symptoms, other comorbidities such as Parkinson disease and cancer, and the desired route of administration.

At the time the patient is discharged, we recommend a careful medication reconciliation and discontinuation of the antipsychotic drug once delirium has resolved. Studies show that at least 26% of antipsychotics initiated in the hospital are continued after discharge.^36,37

Current delirium consensus statements recommend limiting the use of antipsychotics to target patient distress, impediment of care, or safety, because of the putative risks of antipsychotic use in the elderly. However, a growing body of evidence shows that low-dose, time-limited antipsychotic use is safe and effective in the treatment of delirium. In fact, González et al found that delirium is an independent risk factor for death, and each 48-hour increase in delirium is associated with an increased mortality risk of 11%, suggesting that delay in treating delirium may actually increase the risk of death.³⁸

Therefore, we must balance the risks of prescribing antipsychotics in medically vulnerable patients against the increasing burden of evidence supporting the serious risks of morbidity and mortality of delirium, as well as the costs. Much remains to be studied to optimize antipsychotic use in delirium.

Delirium is common in hospitalized patients and contributes to healthcare costs and poor patient outcomes, including death. Its diagnosis and management remain clinically challenging. Although consensus panel guidelines recommend antipsychotic medications to treat delirium when conservative measures fail, few head-to-head trials have been done to tell us which antipsychotic drug to select, and antipsychotic use poses risks in the elderly.

Here, we review the risks and benefits of using antipsychotic drugs to manage delirium and describe an approach to selecting and using 5 commonly used antipsychotics.

SCOPE OF THE PROBLEM

Delirium is common and serious, affecting 11% to 42% of patients hospitalized on general medical wards.¹ The burden to the public and individual patient is extremely high. Delirium has been found to result in an additional $16,303 to $64,421 per delirious patient per year, with a subsequent total 1-year health-attributable cost between $38 billion and $152 billion in the United States.² Furthermore, many patients who become delirious in the hospital lose their independence and are placed in long-term care facilities.³

Although delirium was originally thought to be a time-limited neurocognitive disorder, recent evidence shows that it persists much longer⁴ and that some patients never return to their previous level of function, suggesting that a single episode of delirium can significantly alter the course of an underlying dementia with the dramatic initiation of cognitive decline.³ Most alarmingly, delirium is associated with an increased rate of death.¹  

DSM-5 DEFINITION

According to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5),⁵ delirium is a neurocognitive disorder characterized by the acute onset of disturbance in attention, awareness, and cognition that fluctuates in severity throughout the day and is the direct physiologic consequence of another medical condition. The cognitive impairment seen in delirium is typically global and can affect memory, orientation, language, visuospatial ability, and perception. Other prominent features include psychomotor disturbance, sleep-cycle derangement, and emotional lability.

The pathogenesis of delirium is not clearly delineated but may relate to cholinergic deficiency and dopaminergic excess.

THE FIRST STEPS: NONPHARMACOLOGIC MANAGEMENT

Inouye³ outlined a general 3-part approach to managing delirium:

Identify and address predisposing factors. All patients found to have an acute change in mental status should be evaluated for the underlying cause, with special attention to the most common causes, ie, infection, metabolic derangement, and substance intoxication and withdrawal. A thorough medication reconciliation should also be done to identify medications with psychoactive or anticholinergic effects.

Provide supportive care, eg, addressing volume and nutritional status, mobilizing the patient early, and giving prophylaxis against deep venous thrombosis.

Manage symptoms. Behavioral strategies should be instituted in every delirious patient and should include frequent reorientation, use of observers, encouragement of family involvement, avoidance of physical restraints and Foley catheters, use of vision and hearing aids, and normalizing the sleep-wake cycle.

ANTIPSYCHOTICS: ARE THEY SAFE AND EFFECTIVE?

The US Food and Drug Administration (FDA) has not approved any medications for delirium. However, multiple consensus statements, including those by the American Psychiatric Association,⁶ the Canadian Coalition for Seniors’ Mental Health,⁷ and the UK National Institute for Health and Care Excellence,⁸ advocate for psychopharmacologic management of delirium symptoms in the following situations:

• The patient is in significant distress from his or her symptoms
• The patient poses a safety risk to self or others
• The patient is impeding essential aspects of his or her medical care.

Guidelines from these organizations recommend antipsychotic medications as the first-line drugs for managing delirium symptoms not caused by substance withdrawal. Nevertheless, the use of antipsychotics in the management of delirium remains controversial. While a number of studies suggest these drugs are beneficial,^9–11 others do not.¹² These consensus panels advocate for the judicious use of antipsychotics, limited to the specific situations outlined above.

The use of antipsychotics in elderly and medically complex patients poses risks. One of the most significant safety concerns is increased risk of death due to adverse cardiac events caused by prolongation of the QT interval.

Antipsychotics, QT prolongation, and torsades de pointes

Most antipsychotics have the potential to prolong the time of ventricular depolarization and repolarization and the QT interval to some extent, which can lead to torsades de pointes.¹³ Other risk factors for prolonged QT interval and torsades de pointes include:

• Long QT syndrome (a genetic arrhythmia)
• Female sex
• Old age
• Electrolyte abnormalities (hypokalemia, hypocalcemia, hypomagnesemia)
• Preexisting heart conditions such as bradycardia, left ventricular dysfunction, heart failure, mitral valve prolapse, and previous myocardial infarction
• Medical conditions that cause electrolyte derangements
• Medications, including antiarrhythmics, antibiotics (macrolides, quinolones), antifungals, antimalarials, antiemetics, some opioids (methadone), and most antipsychotics.

Haloperidol. Postmarketing analysis in 2007 found 73 cases of haloperidol-related torsades de pointes. However, many of these were confounded by other QT-prolonging medications and medical conditions.¹⁴

The QT-prolonging effect of haloperidol administered orally or intramuscularly is actually quite small. The equivalent oral dose of 15 mg of haloperidol (assuming 50% bioavailability) given orally or intramuscularly increases the corrected QT interval (QTc) by only 7 to 8 milliseconds. But intravenous haloperidol can cause much more significant QT prolongation: 8 of the 11 reported cases of fatal torsades de pointes occurred when haloperidol was given intravenously.¹⁴ Therefore, the FDA recommends cardiac monitoring for all patients receiving intravenous haloperidol.

Oral olanzapine, risperidone, and quetiapine prolong the QT interval approximately as much as oral haloperidol.

Aripiprazole has not been associated with significant QT prolongation.¹³

The FDA has issued multiple warnings for prescribing antipsychotic medications in the elderly. In 2003, it warned prescribers of increased cerebrovascular adverse events, including stroke, in elderly patients with dementia who were treated with an atypical antipsychotic (risperidone, olanzapine, or aripiprazole) vs placebo.¹⁵

Atypical antipsychotics and risk of death

In 2005, the FDA issued a black-box warning about increased all-cause mortality risk in patients with dementia treated with atypical antipsychotics for behavioral disturbance (relative risk 1.6–1.7).¹⁶

This warning was likely based on a meta-analysis by Schneider et al¹⁷ of trials in which patients with dementia were randomized to receive either an atypical antipsychotic or placebo. The death rate was 3.5% in patients treated with an atypical antipsychotic vs 2.3% in patients treated with placebo, indicating a number needed to harm of 100. The most common causes of death were cardiovascular disease and pneumonia. However, the trials in this meta-analysis included only patients who were prescribed atypical antipsychotics for ongoing management of behavioral disturbances due to dementia in either the outpatient or nursing home setting. None of the trials looked at patients who were prescribed atypical antipsychotics for a limited time in a closely monitored inpatient setting.

Effectiveness of antipsychotics

While several studies since the FDA black-box warning have shown that antipsychotics are safe, the efficacy of these drugs in delirium management remains controversial.

In a 2016 meta-analysis, Kishi et al¹⁸ found that antipsychotics were superior to placebo in terms of response rate (defined as improvement of delirium severity rating scores), with a number needed to treat of 2.

In contrast, a meta-analysis by Neufeld et al¹² found that antipsychotic use was not associated with a change in delirium duration, severity, or length of stay in the hospital or intensive care unit. However, the studies in this meta-analysis varied widely in age range, study design, drug comparison, and treatment strategy (with drugs given as both prophylaxis and treatment). Thus, the results are difficult to interpret.

Kishi et al¹⁸ found no difference in the incidence of death, extrapyramidal symptoms, akathisia, or QT prolongation between patients treated with antipsychotic drugs vs placebo.

In a prospective observational study, Hatta et al¹⁹ followed 2,453 inpatients who became delirious. Only 22 (0.9%) experienced adverse events attributable to antipsychotic use, the most common being aspiration pneumonia (0.7%), followed by cardiovascular events (0.2%). Notably, no patient died of antipsychotic-related events. In this study, the antipsychotic was stopped as soon as the delirium symptoms resolved, in most cases in 3 to 7 days.

Taken together, these studies indicate that despite the risk of QT prolongation with antipsychotic use and increased rates of morbidity with antipsychotic use in dementia, time-limited management of delirium with antipsychotics is effective^9–11 and safe.

SELECTING AND USING ANTIPSYCHOTICS TO TREAT DELIRIUM

Identifying a single preferred agent is difficult, since we lack enough evidence from randomized controlled trials that directly compared the various antipsychotics used in delirium management.

Both typical and atypical antipsychotics are used in clinical practice to manage delirium. The typical antipsychotic most often used is haloperidol, while the most commonly used atypical antipsychotics for delirium include olanzapine, quetiapine, risperidone, and (more recently) aripiprazole.

The American Psychiatric Association guidelines⁶ suggest using haloperidol because it is the antipsychotic that has been most studied for delirium,²⁰ and we have decades of experience with its use. Despite this, recent prospective studies have suggested that the atypical antipsychotics may be better because they have a faster onset of action and lower incidence of extrapyramidal symptoms.^18,21

Because we lack enough head-to-head trials comparing the efficacy of the 5 most commonly used antipsychotics for the management of delirium, and because the prospective trials that do exist show equal efficacy across the antipsychotics studied,²² we suggest considering the unique pharmacologic properties of each drug within the patient’s clinical context when selecting which antipsychotic to use.

Table 1^23–25 summarizes some key characteristics of the 5 most commonly used antipsychotics.

Haloperidol

Haloperidol, a typical antipsychotic, is a potent antagonist of the dopamine D2 receptor.

Haloperidol has the advantage of having the strongest evidence base for use in delirium. In addition, it is available in oral, intravenous, and intramuscular dosage forms, and it has minimal effects on vital signs, negligible anticholinergic activity, and minimal interactions with other medications.²¹

Intravenous haloperidol poses a significant risk of QT prolongation and so should be used judiciously in patients with preexisting cardiac conditions or other risk factors for QT prolongation as outlined above, and with careful cardiac monitoring. Parenteral haloperidol is approximately twice as potent as oral haloperidol.

Some evidence suggests a higher risk of acute dystonia and other extrapyramidal symptoms with haloperidol than with the atypical antipsychotics.^21,26 In contrast, a 2013 prospective study showed that low doses of haloperidol (< 3.5 mg/day) did not result in a greater frequency of extrapyramidal symptoms.²² Nevertheless, if a patient has a history of extrapyramidal symptoms, haloperidol should likely be avoided in favor of an atypical antipsychotic.

Olanzapine, quetiapine, and risperidone are atypical antipsychotics that, like haloperidol, antagonize the dopamine D2 receptor, but also have antagonist action at serotonin, histamine, and alpha-2 receptors. This multireceptor antagonism reduces the risk of extrapyramidal symptoms but increases the risk of orthostatic hypotension.

Quetiapine, in particular, imposes an unacceptably high risk of orthostatic hypotension and so is not recommended for use in delirium in the emergency department.²⁷ Additionally, quetiapine is anticholinergic, raising concerns about constipation and urinary retention.

Although the association between fall risk and antipsychotic use remains controversial,^28,29 a study found that olanzapine conferred a lower fall risk than quetiapine and risperidone.³⁰

Of these drugs, only olanzapine is available in an intramuscular dosage form. Both risperidone and olanzapine are available in dissolvable tablets; however, they are not sublingually absorbed.

Randomized controlled trials have shown that olanzapine is effective in managing cancer-related nausea, and therefore it may be useful in managing delirium in oncology patients.^31,32

Patients with Parkinson disease are exquisitely sensitive to the antidopaminergic effects of antipsychotics but are also vulnerable to delirium, so they present a unique treatment challenge. The agent of choice in patients with Parkinson disease is quetiapine, as multiple trials have shown it has no effect on the motor symptoms of Parkinson disease (reviewed by Desmarais et al in a systematic meta-analysis³³).

Aripiprazole is increasingly used to manage delirium. Its mechanism of action differs from that of the other atypical antipsychotics, as it is a partial dopamine agonist. It is available in oral, orally dissolvable, and intramuscular forms. It appears to be slightly less effective than the other atypical antipsychotics,³⁴ but it may be useful for hypoactive delirium as it is less sedating than the other agents.³⁵ Because its effect on the QT interval is negligible, it may also be favored in patients who have a high baseline QTc or other predisposing factors for torsades de pointes.

BALANCING THE RISKS

Antipsychotic drugs have been shown to be effective and generally safe. Antipsychotics do prolong the QT interval. However, other than with intravenous administration of haloperidol, the absolute effect is minimal. Although large meta-analyses have shown a higher rate of all-cause mortality in elderly outpatients with dementia who are prescribed atypical antipsychotics, an increase in death rates has not been borne out by prospective studies focusing on hospitalized patients who receive low doses of antipsychotics for a limited time.

There are no head-to-head randomized controlled trials comparing the efficacy of all of the 5 most commonly used antipsychotics. Therefore, we suggest considering the unique psychopharmacologic properties of each agent within the patient’s clinical setting, specifically taking into account the risk of cardiac arrhythmia, risk of orthostasis and falls, history of extrapyramidal symptoms, other comorbidities such as Parkinson disease and cancer, and the desired route of administration.

At the time the patient is discharged, we recommend a careful medication reconciliation and discontinuation of the antipsychotic drug once delirium has resolved. Studies show that at least 26% of antipsychotics initiated in the hospital are continued after discharge.^36,37

Current delirium consensus statements recommend limiting the use of antipsychotics to target patient distress, impediment of care, or safety, because of the putative risks of antipsychotic use in the elderly. However, a growing body of evidence shows that low-dose, time-limited antipsychotic use is safe and effective in the treatment of delirium. In fact, González et al found that delirium is an independent risk factor for death, and each 48-hour increase in delirium is associated with an increased mortality risk of 11%, suggesting that delay in treating delirium may actually increase the risk of death.³⁸

Therefore, we must balance the risks of prescribing antipsychotics in medically vulnerable patients against the increasing burden of evidence supporting the serious risks of morbidity and mortality of delirium, as well as the costs. Much remains to be studied to optimize antipsychotic use in delirium.

Delirium is common in hospitalized patients and contributes to healthcare costs and poor patient outcomes, including death. Its diagnosis and management remain clinically challenging. Although consensus panel guidelines recommend antipsychotic medications to treat delirium when conservative measures fail, few head-to-head trials have been done to tell us which antipsychotic drug to select, and antipsychotic use poses risks in the elderly.

Here, we review the risks and benefits of using antipsychotic drugs to manage delirium and describe an approach to selecting and using 5 commonly used antipsychotics.

SCOPE OF THE PROBLEM

Delirium is common and serious, affecting 11% to 42% of patients hospitalized on general medical wards.¹ The burden to the public and individual patient is extremely high. Delirium has been found to result in an additional $16,303 to $64,421 per delirious patient per year, with a subsequent total 1-year health-attributable cost between $38 billion and $152 billion in the United States.² Furthermore, many patients who become delirious in the hospital lose their independence and are placed in long-term care facilities.³

Although delirium was originally thought to be a time-limited neurocognitive disorder, recent evidence shows that it persists much longer⁴ and that some patients never return to their previous level of function, suggesting that a single episode of delirium can significantly alter the course of an underlying dementia with the dramatic initiation of cognitive decline.³ Most alarmingly, delirium is associated with an increased rate of death.¹  

DSM-5 DEFINITION

According to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5),⁵ delirium is a neurocognitive disorder characterized by the acute onset of disturbance in attention, awareness, and cognition that fluctuates in severity throughout the day and is the direct physiologic consequence of another medical condition. The cognitive impairment seen in delirium is typically global and can affect memory, orientation, language, visuospatial ability, and perception. Other prominent features include psychomotor disturbance, sleep-cycle derangement, and emotional lability.

The pathogenesis of delirium is not clearly delineated but may relate to cholinergic deficiency and dopaminergic excess.

THE FIRST STEPS: NONPHARMACOLOGIC MANAGEMENT

Inouye³ outlined a general 3-part approach to managing delirium:

Identify and address predisposing factors. All patients found to have an acute change in mental status should be evaluated for the underlying cause, with special attention to the most common causes, ie, infection, metabolic derangement, and substance intoxication and withdrawal. A thorough medication reconciliation should also be done to identify medications with psychoactive or anticholinergic effects.

Provide supportive care, eg, addressing volume and nutritional status, mobilizing the patient early, and giving prophylaxis against deep venous thrombosis.

Manage symptoms. Behavioral strategies should be instituted in every delirious patient and should include frequent reorientation, use of observers, encouragement of family involvement, avoidance of physical restraints and Foley catheters, use of vision and hearing aids, and normalizing the sleep-wake cycle.

ANTIPSYCHOTICS: ARE THEY SAFE AND EFFECTIVE?

The US Food and Drug Administration (FDA) has not approved any medications for delirium. However, multiple consensus statements, including those by the American Psychiatric Association,⁶ the Canadian Coalition for Seniors’ Mental Health,⁷ and the UK National Institute for Health and Care Excellence,⁸ advocate for psychopharmacologic management of delirium symptoms in the following situations:

• The patient is in significant distress from his or her symptoms
• The patient poses a safety risk to self or others
• The patient is impeding essential aspects of his or her medical care.

Guidelines from these organizations recommend antipsychotic medications as the first-line drugs for managing delirium symptoms not caused by substance withdrawal. Nevertheless, the use of antipsychotics in the management of delirium remains controversial. While a number of studies suggest these drugs are beneficial,^9–11 others do not.¹² These consensus panels advocate for the judicious use of antipsychotics, limited to the specific situations outlined above.

The use of antipsychotics in elderly and medically complex patients poses risks. One of the most significant safety concerns is increased risk of death due to adverse cardiac events caused by prolongation of the QT interval.

Antipsychotics, QT prolongation, and torsades de pointes

Most antipsychotics have the potential to prolong the time of ventricular depolarization and repolarization and the QT interval to some extent, which can lead to torsades de pointes.¹³ Other risk factors for prolonged QT interval and torsades de pointes include:

• Long QT syndrome (a genetic arrhythmia)
• Female sex
• Old age
• Electrolyte abnormalities (hypokalemia, hypocalcemia, hypomagnesemia)
• Preexisting heart conditions such as bradycardia, left ventricular dysfunction, heart failure, mitral valve prolapse, and previous myocardial infarction
• Medical conditions that cause electrolyte derangements
• Medications, including antiarrhythmics, antibiotics (macrolides, quinolones), antifungals, antimalarials, antiemetics, some opioids (methadone), and most antipsychotics.

Haloperidol. Postmarketing analysis in 2007 found 73 cases of haloperidol-related torsades de pointes. However, many of these were confounded by other QT-prolonging medications and medical conditions.¹⁴

The QT-prolonging effect of haloperidol administered orally or intramuscularly is actually quite small. The equivalent oral dose of 15 mg of haloperidol (assuming 50% bioavailability) given orally or intramuscularly increases the corrected QT interval (QTc) by only 7 to 8 milliseconds. But intravenous haloperidol can cause much more significant QT prolongation: 8 of the 11 reported cases of fatal torsades de pointes occurred when haloperidol was given intravenously.¹⁴ Therefore, the FDA recommends cardiac monitoring for all patients receiving intravenous haloperidol.

Oral olanzapine, risperidone, and quetiapine prolong the QT interval approximately as much as oral haloperidol.

Aripiprazole has not been associated with significant QT prolongation.¹³

The FDA has issued multiple warnings for prescribing antipsychotic medications in the elderly. In 2003, it warned prescribers of increased cerebrovascular adverse events, including stroke, in elderly patients with dementia who were treated with an atypical antipsychotic (risperidone, olanzapine, or aripiprazole) vs placebo.¹⁵

Atypical antipsychotics and risk of death

In 2005, the FDA issued a black-box warning about increased all-cause mortality risk in patients with dementia treated with atypical antipsychotics for behavioral disturbance (relative risk 1.6–1.7).¹⁶

This warning was likely based on a meta-analysis by Schneider et al¹⁷ of trials in which patients with dementia were randomized to receive either an atypical antipsychotic or placebo. The death rate was 3.5% in patients treated with an atypical antipsychotic vs 2.3% in patients treated with placebo, indicating a number needed to harm of 100. The most common causes of death were cardiovascular disease and pneumonia. However, the trials in this meta-analysis included only patients who were prescribed atypical antipsychotics for ongoing management of behavioral disturbances due to dementia in either the outpatient or nursing home setting. None of the trials looked at patients who were prescribed atypical antipsychotics for a limited time in a closely monitored inpatient setting.

Effectiveness of antipsychotics

While several studies since the FDA black-box warning have shown that antipsychotics are safe, the efficacy of these drugs in delirium management remains controversial.

In a 2016 meta-analysis, Kishi et al¹⁸ found that antipsychotics were superior to placebo in terms of response rate (defined as improvement of delirium severity rating scores), with a number needed to treat of 2.

In contrast, a meta-analysis by Neufeld et al¹² found that antipsychotic use was not associated with a change in delirium duration, severity, or length of stay in the hospital or intensive care unit. However, the studies in this meta-analysis varied widely in age range, study design, drug comparison, and treatment strategy (with drugs given as both prophylaxis and treatment). Thus, the results are difficult to interpret.

Kishi et al¹⁸ found no difference in the incidence of death, extrapyramidal symptoms, akathisia, or QT prolongation between patients treated with antipsychotic drugs vs placebo.

In a prospective observational study, Hatta et al¹⁹ followed 2,453 inpatients who became delirious. Only 22 (0.9%) experienced adverse events attributable to antipsychotic use, the most common being aspiration pneumonia (0.7%), followed by cardiovascular events (0.2%). Notably, no patient died of antipsychotic-related events. In this study, the antipsychotic was stopped as soon as the delirium symptoms resolved, in most cases in 3 to 7 days.

Taken together, these studies indicate that despite the risk of QT prolongation with antipsychotic use and increased rates of morbidity with antipsychotic use in dementia, time-limited management of delirium with antipsychotics is effective^9–11 and safe.

SELECTING AND USING ANTIPSYCHOTICS TO TREAT DELIRIUM

Identifying a single preferred agent is difficult, since we lack enough evidence from randomized controlled trials that directly compared the various antipsychotics used in delirium management.

Both typical and atypical antipsychotics are used in clinical practice to manage delirium. The typical antipsychotic most often used is haloperidol, while the most commonly used atypical antipsychotics for delirium include olanzapine, quetiapine, risperidone, and (more recently) aripiprazole.

The American Psychiatric Association guidelines⁶ suggest using haloperidol because it is the antipsychotic that has been most studied for delirium,²⁰ and we have decades of experience with its use. Despite this, recent prospective studies have suggested that the atypical antipsychotics may be better because they have a faster onset of action and lower incidence of extrapyramidal symptoms.^18,21

Because we lack enough head-to-head trials comparing the efficacy of the 5 most commonly used antipsychotics for the management of delirium, and because the prospective trials that do exist show equal efficacy across the antipsychotics studied,²² we suggest considering the unique pharmacologic properties of each drug within the patient’s clinical context when selecting which antipsychotic to use.

Table 1^23–25 summarizes some key characteristics of the 5 most commonly used antipsychotics.

Haloperidol

Haloperidol, a typical antipsychotic, is a potent antagonist of the dopamine D2 receptor.

Haloperidol has the advantage of having the strongest evidence base for use in delirium. In addition, it is available in oral, intravenous, and intramuscular dosage forms, and it has minimal effects on vital signs, negligible anticholinergic activity, and minimal interactions with other medications.²¹

Intravenous haloperidol poses a significant risk of QT prolongation and so should be used judiciously in patients with preexisting cardiac conditions or other risk factors for QT prolongation as outlined above, and with careful cardiac monitoring. Parenteral haloperidol is approximately twice as potent as oral haloperidol.

Some evidence suggests a higher risk of acute dystonia and other extrapyramidal symptoms with haloperidol than with the atypical antipsychotics.^21,26 In contrast, a 2013 prospective study showed that low doses of haloperidol (< 3.5 mg/day) did not result in a greater frequency of extrapyramidal symptoms.²² Nevertheless, if a patient has a history of extrapyramidal symptoms, haloperidol should likely be avoided in favor of an atypical antipsychotic.

Olanzapine, quetiapine, and risperidone are atypical antipsychotics that, like haloperidol, antagonize the dopamine D2 receptor, but also have antagonist action at serotonin, histamine, and alpha-2 receptors. This multireceptor antagonism reduces the risk of extrapyramidal symptoms but increases the risk of orthostatic hypotension.

Quetiapine, in particular, imposes an unacceptably high risk of orthostatic hypotension and so is not recommended for use in delirium in the emergency department.²⁷ Additionally, quetiapine is anticholinergic, raising concerns about constipation and urinary retention.

Although the association between fall risk and antipsychotic use remains controversial,^28,29 a study found that olanzapine conferred a lower fall risk than quetiapine and risperidone.³⁰

Of these drugs, only olanzapine is available in an intramuscular dosage form. Both risperidone and olanzapine are available in dissolvable tablets; however, they are not sublingually absorbed.

Randomized controlled trials have shown that olanzapine is effective in managing cancer-related nausea, and therefore it may be useful in managing delirium in oncology patients.^31,32

Patients with Parkinson disease are exquisitely sensitive to the antidopaminergic effects of antipsychotics but are also vulnerable to delirium, so they present a unique treatment challenge. The agent of choice in patients with Parkinson disease is quetiapine, as multiple trials have shown it has no effect on the motor symptoms of Parkinson disease (reviewed by Desmarais et al in a systematic meta-analysis³³).

Aripiprazole is increasingly used to manage delirium. Its mechanism of action differs from that of the other atypical antipsychotics, as it is a partial dopamine agonist. It is available in oral, orally dissolvable, and intramuscular forms. It appears to be slightly less effective than the other atypical antipsychotics,³⁴ but it may be useful for hypoactive delirium as it is less sedating than the other agents.³⁵ Because its effect on the QT interval is negligible, it may also be favored in patients who have a high baseline QTc or other predisposing factors for torsades de pointes.

BALANCING THE RISKS

Antipsychotic drugs have been shown to be effective and generally safe. Antipsychotics do prolong the QT interval. However, other than with intravenous administration of haloperidol, the absolute effect is minimal. Although large meta-analyses have shown a higher rate of all-cause mortality in elderly outpatients with dementia who are prescribed atypical antipsychotics, an increase in death rates has not been borne out by prospective studies focusing on hospitalized patients who receive low doses of antipsychotics for a limited time.

There are no head-to-head randomized controlled trials comparing the efficacy of all of the 5 most commonly used antipsychotics. Therefore, we suggest considering the unique psychopharmacologic properties of each agent within the patient’s clinical setting, specifically taking into account the risk of cardiac arrhythmia, risk of orthostasis and falls, history of extrapyramidal symptoms, other comorbidities such as Parkinson disease and cancer, and the desired route of administration.

At the time the patient is discharged, we recommend a careful medication reconciliation and discontinuation of the antipsychotic drug once delirium has resolved. Studies show that at least 26% of antipsychotics initiated in the hospital are continued after discharge.^36,37

Current delirium consensus statements recommend limiting the use of antipsychotics to target patient distress, impediment of care, or safety, because of the putative risks of antipsychotic use in the elderly. However, a growing body of evidence shows that low-dose, time-limited antipsychotic use is safe and effective in the treatment of delirium. In fact, González et al found that delirium is an independent risk factor for death, and each 48-hour increase in delirium is associated with an increased mortality risk of 11%, suggesting that delay in treating delirium may actually increase the risk of death.³⁸

Therefore, we must balance the risks of prescribing antipsychotics in medically vulnerable patients against the increasing burden of evidence supporting the serious risks of morbidity and mortality of delirium, as well as the costs. Much remains to be studied to optimize antipsychotic use in delirium.

On examination, her lung fields were clear, with no audible murmurs, and she had no lower-extremity edema. Her oxygen saturation was 98% on room air.

BREAST CALCIFICATIONS CAN MIMIC PULMONARY NODULES

Diffuse bilateral calcifications on mammography are typically benign and represent either dermal calcification (spherical lucent- centered calcification that develops from a degenerative metaplastic process) or fibrocystic changes.¹ Up to 10% of women have fibroadenomas, and 19% of fibroadenomas have microcalcifications.^2–4 Therefore, given the high prevalence, calcified breast masses should be considered in the differential diagnosis when evaluating initial chest radiographs in women.

Calcifications in the breast can overlie the lung fields and mimic pulmonary nodules. When assessing pulmonary nodules, prior imaging of the chest should always be assessed if available to determine if a lesion is new or has remained stable.

Given our patient’s age and 35-pack-year history of smoking, apparent pulmonary lesions caused concern and prompted chest CT to clarify the diagnosis. However, if the patient has no risk factors for lung malignancy, it can be safe to proceed with mammography.

By including breast calcifications in the differential diagnosis of apparent pulmonary nodules on chest radiography, the clinician can approach the case differently and inquire about a history of fibroadenomas and prior mammograms before pursuing a further workup. This can avoid unnecessary radiation exposure, the costs of CT, and apprehension in the patient raised by unwarranted concern for malignancy.

On examination, her lung fields were clear, with no audible murmurs, and she had no lower-extremity edema. Her oxygen saturation was 98% on room air.

BREAST CALCIFICATIONS CAN MIMIC PULMONARY NODULES

Diffuse bilateral calcifications on mammography are typically benign and represent either dermal calcification (spherical lucent- centered calcification that develops from a degenerative metaplastic process) or fibrocystic changes.¹ Up to 10% of women have fibroadenomas, and 19% of fibroadenomas have microcalcifications.^2–4 Therefore, given the high prevalence, calcified breast masses should be considered in the differential diagnosis when evaluating initial chest radiographs in women.

Calcifications in the breast can overlie the lung fields and mimic pulmonary nodules. When assessing pulmonary nodules, prior imaging of the chest should always be assessed if available to determine if a lesion is new or has remained stable.

Given our patient’s age and 35-pack-year history of smoking, apparent pulmonary lesions caused concern and prompted chest CT to clarify the diagnosis. However, if the patient has no risk factors for lung malignancy, it can be safe to proceed with mammography.

By including breast calcifications in the differential diagnosis of apparent pulmonary nodules on chest radiography, the clinician can approach the case differently and inquire about a history of fibroadenomas and prior mammograms before pursuing a further workup. This can avoid unnecessary radiation exposure, the costs of CT, and apprehension in the patient raised by unwarranted concern for malignancy.

On examination, her lung fields were clear, with no audible murmurs, and she had no lower-extremity edema. Her oxygen saturation was 98% on room air.

BREAST CALCIFICATIONS CAN MIMIC PULMONARY NODULES

Diffuse bilateral calcifications on mammography are typically benign and represent either dermal calcification (spherical lucent- centered calcification that develops from a degenerative metaplastic process) or fibrocystic changes.¹ Up to 10% of women have fibroadenomas, and 19% of fibroadenomas have microcalcifications.^2–4 Therefore, given the high prevalence, calcified breast masses should be considered in the differential diagnosis when evaluating initial chest radiographs in women.

Calcifications in the breast can overlie the lung fields and mimic pulmonary nodules. When assessing pulmonary nodules, prior imaging of the chest should always be assessed if available to determine if a lesion is new or has remained stable.

Given our patient’s age and 35-pack-year history of smoking, apparent pulmonary lesions caused concern and prompted chest CT to clarify the diagnosis. However, if the patient has no risk factors for lung malignancy, it can be safe to proceed with mammography.

By including breast calcifications in the differential diagnosis of apparent pulmonary nodules on chest radiography, the clinician can approach the case differently and inquire about a history of fibroadenomas and prior mammograms before pursuing a further workup. This can avoid unnecessary radiation exposure, the costs of CT, and apprehension in the patient raised by unwarranted concern for malignancy.

Acute pancreatitis accounted for more than 300,000 admissions and $2.6 billion in associated healthcare costs in the United States in 2012.¹ First-line management is early aggressive fluid resuscitation and analgesics for pain control. Guidelines recommend estimating the clinical severity of each attack using a validated scoring system such as the Bedside Index of Severity in Acute Pancreatitis.² Clinically severe pancreatitis is associated with necrosis.

Acute pancreatitis results from inappropriate activation of zymogens and subsequent auto­digestion of the pancreas by its own enzymes. Though necrotizing pancreatitis is thought to be an ischemic complication, its pathogenesis is not completely understood. Necrosis increases the morbidity and mortality risk of acute pancreatitis because of its association with organ failure and infectious complications. As such, patients with necrotizing pancreatitis may need admission to the intensive care unit, nutritional support, antibiotics, and radiologic, endoscopic, or surgical interventions.

Here, we review current evidence regarding the diagnosis and management of necrotizing pancreatitis.

PROPER TERMINOLOGY HELPS COLLABORATION

Managing necrotizing pancreatitis requires the combined efforts of internists, gastroenterologists, radiologists, and surgeons. This collaboration is aided by proper terminology.

A classification system was devised in Atlanta, GA, in 1992 to facilitate communication and interdisciplinary collaboration.³ Severe pancreatitis was differentiated from mild by the presence of organ failure or the complications of pseudocyst, necrosis, or abscess.

The original Atlanta classification had several limitations. First, the terminology for fluid collections was ambiguous and frequently misused. Second, the assessment of clinical severity required either the Ranson score or the Acute Physiology and Chronic Health Evaluation II score, both of which are complex and have other limitations. Finally, advances in imaging and treatment have rendered the original Atlanta nomenclature obsolete.

In 2012, the Acute Pancreatitis Classification Working Group issued a revised Atlanta classification that modernized the terminology pertaining to natural history, severity, imaging features, and complications. It divides the natural course of acute pancreatitis into early and late phases.⁴

Early vs late phase

In the early phase, findings on computed tomography (CT) neither correlate with clinical severity nor alter clinical management.⁶ Thus, early imaging is not indicated unless there is diagnostic uncertainty, lack of response to appropriate treatment, or sudden deterioration.

Moderate pancreatitis describes patients with pancreatic necrosis with or without transient organ failure (organ dysfunction for ≤ 48 hours).

Severe pancreatitis is defined by pancreatic necrosis and persistent organ dysfunction.⁴ It may be accompanied by pancreatic and peripancreatic fluid collections; bacteremia and sepsis can occur in association with infection of necrotic collections.

Interstitial edematous pancreatitis vs necrotizing pancreatitis

The revised Atlanta classification maintains the original classification of acute pancreatitis into 2 main categories: interstitial edematous pancreatitis and necrotizing pancreatitis.

Necrotizing pancreatitis is further divided into 3 subtypes based on extent and location of necrosis:

• Parenchymal necrosis alone (5% of cases)
• Necrosis of peripancreatic fat alone (20%)
• Necrosis of both parenchyma and peripancreatic fat (75%).

Peripancreatic involvement is commonly found in the mesentery, peripancreatic and distant retroperitoneum, and lesser sac.

Of the three subtypes, peripancreatic necrosis has the best prognosis. However, all of the subtypes of necrotizing pancreatitis are associated with poorer outcomes than interstitial edematous pancreatitis.

Fluid collections

Acute pancreatic fluid collections contain exclusively nonsolid components without an inflammatory wall and are typically found in the peripancreatic fat. These collections often resolve without intervention as the patient recovers. If they persist beyond 4 weeks and develop a nonepithelialized, fibrous wall, they become pseudocysts. Intervention is generally not recommended for pseudocysts unless they are symptomatic.

Radiographic imaging is not usually necessary to diagnose acute pancreatitis. However, it can be a valuable tool to clarify an ambiguous presentation, determine severity, and identify complications.

The timing and appropriate type of imaging are integral to obtaining useful data. Any imaging obtained in acute pancreatitis to evaluate necrosis should be performed at least 3 to 5 days from the initial symptom onset; if imaging is obtained before 72 hours, necrosis cannot be confidently excluded.⁸

COMPUTED TOMOGRAPHY

CT is the imaging test of choice when evaluating acute pancreatitis. In addition, almost all percutaneous interventions are performed with CT guidance. The Balthazar score is the most well-known CT severity index. It is calculated based on the degree of inflammation, acute fluid collections, and parenchymal necrosis.⁹ However, a modified severity index incorporates extrapancreatic complications such as ascites and vascular compromise and was found to more strongly correlate with outcomes than the standard Balthazar score.¹⁰

Contrast-enhanced CT is performed in 2 phases:

The pancreatic parenchymal phase

The pancreatic parenchymal or late arterial phase is obtained approximately 40 to 45 seconds after the start of the contrast bolus. It is used to detect necrosis in the early phase of acute pancreatitis and to assess the peripancreatic arteries for pseudoaneurysms in the late phase of acute pancreatitis.¹¹

Pancreatic necrosis appears as an area of decreased parenchymal enhancement, either well-defined or heterogeneous. The normal pancreatic parenchyma has a postcontrast enhancement pattern similar to that of the spleen. Parenchyma that does not enhance to the same degree is considered necrotic. The severity of necrosis is graded based on the percentage of the pancreas involved (< 30%, 30%–50%, or > 50%), and a higher percentage correlates with a worse outcome.^12,13

Peripancreatic necrosis is harder to detect, as there is no method to assess fat enhancement as there is with pancreatic parenchymal enhancement. In general, radiologists assume that heterogeneous peripancreatic changes, including areas of fat, fluid, and soft tissue attenuation, are consistent with peripancreatic necrosis. After 7 to 10 days, if these changes become more homogeneous and confluent with a more mass-like process, peripancreatic necrosis can be more confidently identified.^12,13

The portal venous phase

The later, portal venous phase of the scan is obtained approximately 70 seconds after the start of the contrast bolus. It is used to detect and characterize fluid collections and venous complications of the disease.

Drawbacks of CT

A drawback of CT is the need for iodinated intravenous contrast media, which in severely ill patients may precipitate or worsen pre-existing acute kidney injury.

Further, several studies have shown that findings on CT rarely alter the management of patients in the early phase of acute pancreatitis and in fact may be an overuse of medical resources.¹⁴ Unless there are confounding clinical signs or symptoms, CT should be delayed for at least 72 hours.^9,10,14,15

MAGNETIC RESONANCE IMAGING

Magnetic resonance imaging (MRI) is not a first-line imaging test in this disease because it is not as available as CT and takes longer to perform—20 to 30 minutes. The patient must be evaluated for candidacy, as it is difficult for acutely ill patients to tolerate an examination that takes this long and requires them to hold their breath multiple times.

MRI is an appropriate alternative in patients who are pregnant or who have severe iodinated-contrast allergy. While contrast is necessary to detect pancreatic necrosis with CT, MRI can detect necrosis without the need for contrast in patients with acute kidney injury or severe chronic kidney disease. Also, MRI may be better in complicated cases requiring repeated imaging because it does not expose the patient to radiation.

On MRI, pancreatic necrosis appears as a heterogeneous area, owing to its liquid and solid components. Liquid components appear hyperintense, and solid components hypointense, on T2 fluid-weighted imaging. This ability to differentiate the components of a walled-off pancreatic necrosis can be useful in determining whether a collection requires drainage or debridement. MRI is also more sensitive for hemorrhagic complications, best seen on T1 fat-weighted images.^12,16

Magnetic resonance cholangiopancreatography is an excellent method for ductal evaluation through heavily T2-weighted imaging. It is more sensitive than CT for detecting common bile duct stones and can also detect pancreatic duct strictures or extravasation into fluid collections.¹⁶

SUPPORTIVE MANAGEMENT OF EARLY NECROTIZING PANCREATITIS

In the early phase of necrotizing pancreatitis, management is supportive with the primary aim of preventing intravascular volume depletion. Aggressive fluid resuscitation in the first 48 to 72 hours, pain control, and bowel rest are the mainstays of supportive therapy. Intensive care may be necessary if organ failure and hemodynamic instability accompany necrotizing pancreatitis.

Prophylactic antibiotic and antifungal therapy to prevent infected necrosis has been controversial. Recent studies of its utility have not yielded supportive results, and the American College of Gastroenterology and the Infectious Diseases Society of America no longer recommend it.^9,17 These medications should not be given unless concomitant cholangitis or extrapancreatic infection is clinically suspected.

Early enteral nutrition is recommended in patients in whom pancreatitis is predicted to be severe and in those not expected to resume oral intake within 5 to 7 days. Enteral nutrition most commonly involves bedside or endoscopic placement of a nasojejunal feeding tube and collaboration with a nutritionist to determine protein-caloric requirements.

Compared with enteral nutrition, total parenteral nutrition is associated with higher rates of infection, multiorgan dysfunction and failure, and death.¹⁸

Necrotizing pancreatitis is a defining complication of acute pancreatitis, and its presence alone indicates greater severity. However, superimposed complications may further worsen outcomes.

Infected pancreatic necrosis

Infection occurs in approximately 20% of patients with necrotizing pancreatitis and confers a mortality rate of 20% to 50%.¹⁹ Infected pancreatic necrosis occurs when gut organisms translocate into the nearby necrotic pancreatic and peripancreatic tissue. The most commonly identified organisms include Escherichia coli and Enterococcus species.²⁰

This complication usually manifests 2 to 4 weeks after symptom onset; earlier onset is uncommon to rare. It should be considered when the systemic inflammatory response syndrome persists or recurs after 10 days to 2 weeks. Systemic inflammatory response syndrome is also common in sterile necrotizing pancreatitis and sometimes in interstitial pancreatitis, particularly during the first week. However, its sudden appearance or resurgence, high spiking fevers, or worsening organ failure in the later phase (2–4 weeks) of pancreatitis should heighten suspicion of infected pancreatic necrosis.

Imaging may also help diagnose infection, and the presence of gas within a collection or region of necrosis is highly specific. However, the presence of gas is not completely sensitive for infection, as it is seen in only 12% to 22% of infected cases.

Before minimally invasive techniques became available, the diagnosis of infected pancreatic necrosis was confirmed by percutaneous CT-guided aspiration of the necrotic mass or collection for Gram stain and culture.

Antibiotic therapy is indicated in confirmed or suspected cases of infected pancreatic necrosis. Antibiotics with gram-negative coverage and appropriate penetration such as carbapenems, metronidazole, fluoroquinolones, and selected cephalosporins are most commonly used. Meropenem is the antibiotic of choice at our institution.

CT-guided fine-needle aspiration is often done if suspected infected pancreatic necrosis fails to respond to empiric antibiotic therapy.

Debridement or drainage. Generally, the diagnosis or suspicion of infected pancreatic necrosis (suggestive signs are high fever, elevated white blood cell count, and sepsis) warrants an intervention to debride or drain infected pancreatic tissue and control sepsis.²¹

While source control is integral to the successful treatment of infected pancreatic necrosis, antibiotic therapy may provide a bridge to intervention for critically ill patients by suppressing bacteremia and subsequent sepsis. A 2013 meta-analysis found that 324 of 409 patients with suspected infected pancreatic necrosis were successfully stabilized with antibiotic treatment.^21,22 The trend toward conservative management and promising outcomes with antibiotic therapy alone or with minimally invasive techniques has lessened the need for diagnostic CT-guided fine-needle aspiration.

Hemorrhage

Spontaneous hemorrhage into pancreatic necrosis is a rare but life-threatening complication. Because CT is almost always performed with contrast enhancement, this complication is rarely identified with imaging. The diagnosis is made by noting a drop in hemoglobin and hematocrit.

Hemorrhage into the retroperitoneum or the peritoneal cavity, or both, can occur when an inflammatory process erodes into a nearby artery. Luminal gastrointestinal bleeding can occur from gastric varices arising from splenic vein thrombosis and resulting left-sided portal hypertension, or from pseudoaneurysms. These can also bleed into the pancreatic duct (hemosuccus pancreaticus). Pseudoaneurysm is a later complication that occurs when an arterial wall (most commonly the splenic or gastroduodenal artery) is weakened by pancreatic enzymes.²³

Prompt recognition of hemorrhagic events and consultation with an interventional radiologist or surgeon are required to prevent death.

Inflammation and abdominal compartment syndrome

Inflammation from necrotizing pancreatitis can cause further complications by blocking nearby structures. Reported complications include jaundice from biliary compression, hydronephrosis from ureteral compression, bowel obstruction, and gastric outlet obstruction.

Abdominal compartment syndrome is an increasingly recognized complication of acute pancreatitis. Abdominal pressure can rise due to a number of factors, including fluid collections, ascites, ileus, and overly aggressive fluid resuscitation.²⁴ Elevated abdominal pressure is associated with complications such as decreased respiratory compliance, increased peak airway pressure, decreased cardiac preload, hypotension, mesenteric and intestinal ischemia, feeding intolerance, and lower-extremity ischemia and thrombosis.

Patients with necrotizing pancreatitis who have abdominal compartment syndrome have a mortality rate 5 times higher than patients without abdominal compartment syndrome.²⁵

Abdominal pressures should be monitored using a bladder pressure sensor in critically ill or ventilated patients with acute pancreatitis. If the abdominal pressure rises above 20 mm Hg, medical and surgical interventions should be offered in a stepwise fashion to decrease it. Interventions include decompression by nasogastric and rectal tube, sedation or paralysis to relax abdominal wall tension, minimization of intravenous fluids, percutaneous drainage of ascites, and (rarely) surgical midline or subcostal laparotomy.

The treatment of necrotizing pancreatitis has changed rapidly, thanks to a growing experience with minimally invasive techniques.

Indications for intervention

Infected pancreatic necrosis is the primary indication for surgical, percutaneous, or endoscopic intervention.

In sterile necrosis, the threshold for intervention is less clear, and intervention is often reserved for patients who fail to clinically improve or who have intractable abdominal pain, gastric outlet obstruction, or fistulating disease.²⁶

In asymptomatic cases, intervention is almost never indicated regardless of the location or size of the necrotic area.

In walled-off pancreatic necrosis, less-invasive and less-morbid interventions such as endoscopic or percutaneous drainage or video-assisted retroperitoneal debridement can be done.

Timing of intervention

In the past, delaying intervention was thought to increase the risk of death. However, multiple studies have found that outcomes are often worse if intervention is done early, likely due to the lack of a fully formed fibrous wall or demarcation of the necrotic area.²⁷

If the patient remains clinically stable, it is best to delay intervention until at least 4 weeks after the index event to achieve optimal outcomes. Delay can often be achieved by antibiotic treatment to suppress bacteremia and endoscopic or percutaneous drainage of infected collections to control sepsis.

Open surgery

The gold-standard intervention for infected pancreatic necrosis or symptomatic sterile walled-off pancreatic necrosis is open necrosectomy. This involves exploratory laparotomy with blunt debridement of all visible necrotic pancreatic tissue.

Methods to facilitate later evacuation of residual infected fluid and debris vary widely. Multiple large-caliber drains can be placed to facilitate irrigation and drainage before closure of the abdominal fascia. As infected pancreatic necrosis carries the risk of contaminating the peritoneal cavity, the skin is often left open to heal by secondary intention. An interventional radiologist is frequently enlisted to place, exchange, or downsize drainage catheters.

Infected pancreatic necrosis or symptomatic sterile walled-off pancreatic necrosis often requires more than one operation to achieve satisfactory debridement.

The goals of open necrosectomy are to remove nonviable tissue and infection, preserve viable pancreatic tissue, eliminate fistulous connections, and minimize damage to local organs and vasculature.

Minimally invasive techniques

Video-assisted retroperitoneal debridement has been described as a hybrid between endoscopic and open retroperitoneal debridement.²⁸ This technique requires first placing a percutaneous catheter into the necrotic area through the left flank to create a retroperitoneal tract. A 5-cm incision is made and the necrotic space is entered using the drain for guidance. Necrotic tissue is carefully debrided under direct vision using a combination of forceps, irrigation, and suction. A laparoscopic port can also be introduced into the incision when the procedure can no longer be continued under direct vision.^29,30

Although not all patients are candidates for minimal-access surgery, it remains an evolving surgical option.

Endoscopic transmural debridement is another option for infected pancreatic necrosis and symptomatic walled-off pancreatic necrosis. Depending on the location of the necrotic area, an echoendoscope is passed to either the stomach or duodenum. Guided by endoscopic ultrasonography, a needle is passed into the collection, allowing subsequent fistula creation and stenting for internal drainage or debridement. In the past, this process required several steps, multiple devices, fluoroscopic guidance, and considerable time. But newer endoscopic lumen-apposing metal stents have been developed that can be placed in a single step without fluoroscopy. A slimmer endoscope can then be introduced into the necrotic cavity via the stent, and the necrotic debris can be debrided with endoscopic baskets, snares, forceps, and irrigation.^9,31

Similar to surgical necrosectomy, satisfactory debridement is not often obtained with a single procedure; 2 to 5 endoscopic procedures may be needed to achieve resolution. However, the luminal approach in endoscopic necrosectomy avoids the significant morbidity of major abdominal surgery and the potential for pancreaticocutaneous fistulae that may occur with drains.

In a randomized trial comparing endoscopic necrosectomy vs surgical necrosectomy (video-assisted retroperitoneal debridement and exploratory laparotomy),³² endoscopic necrosectomy showed less inflammatory response than surgical necrosectomy and had a lower risk of new-onset organ failure, bleeding, fistula formation, and death.³²

Selecting the best intervention for the individual patient

Given the multiple available techniques, selecting the best intervention for individual patients can be challenging. A team approach with input from a gastroenterologist, surgeon, and interventional radiologist is best when determining which technique would best suit each patient.

Surgical necrosectomy is still the treatment of choice for unstable patients with infected pancreatic necrosis or multiple, inaccessible collections, but current evidence suggests a different approach in stable infected pancreatic necrosis and symptomatic sterile walled-off pancreatic necrosis.

The Dutch Pancreatitis Group²⁸ randomized 88 patients with infected pancreatic necrosis or symptomatic walled-off pancreatic necrosis to open necrosectomy or a minimally invasive “step-up” approach consisting of up to 2 percutaneous drainage or endoscopic debridement procedures before escalation to video-assisted retroperitoneal debridement. The step-up approach resulted in lower rates of morbidity and death than surgical necrosectomy as first-line treatment. Furthermore, some patients in the step-up group avoided the need for surgery entirely.³⁰

Necrosis significantly increases rates of morbidity and mortality in acute pancreatitis. Hospitalists, general internists, and general surgeons are all on the front lines in identifying severe cases and consulting the appropriate specialists for optimal multidisciplinary care. Selective and appropriate timing of radiologic imaging is key, and a vital tool in the management of necrotizing pancreatitis.

While the primary indication for intervention is infected pancreatic necrosis, additional indications are symptomatic walled-off pancreatic necrosis secondary to intractable abdominal pain, bowel obstruction, and failure to thrive. As a result of improving technology and inpatient care, these patients may present with intractable symptoms in the outpatient setting rather than the inpatient setting. The onus is on the primary care physician to maintain a high level of suspicion and refer these patients to subspecialists as appropriate.

Open surgical necrosectomy remains an important approach for care of infected pancreatic necrosis or patients with intractable symptoms. A step-up approach starting with a minimally invasive procedure and escalating if the initial intervention is unsuccessful is gradually becoming the standard of care.

Acute pancreatitis accounted for more than 300,000 admissions and $2.6 billion in associated healthcare costs in the United States in 2012.¹ First-line management is early aggressive fluid resuscitation and analgesics for pain control. Guidelines recommend estimating the clinical severity of each attack using a validated scoring system such as the Bedside Index of Severity in Acute Pancreatitis.² Clinically severe pancreatitis is associated with necrosis.

Acute pancreatitis results from inappropriate activation of zymogens and subsequent auto­digestion of the pancreas by its own enzymes. Though necrotizing pancreatitis is thought to be an ischemic complication, its pathogenesis is not completely understood. Necrosis increases the morbidity and mortality risk of acute pancreatitis because of its association with organ failure and infectious complications. As such, patients with necrotizing pancreatitis may need admission to the intensive care unit, nutritional support, antibiotics, and radiologic, endoscopic, or surgical interventions.

Here, we review current evidence regarding the diagnosis and management of necrotizing pancreatitis.

PROPER TERMINOLOGY HELPS COLLABORATION

Managing necrotizing pancreatitis requires the combined efforts of internists, gastroenterologists, radiologists, and surgeons. This collaboration is aided by proper terminology.

A classification system was devised in Atlanta, GA, in 1992 to facilitate communication and interdisciplinary collaboration.³ Severe pancreatitis was differentiated from mild by the presence of organ failure or the complications of pseudocyst, necrosis, or abscess.

The original Atlanta classification had several limitations. First, the terminology for fluid collections was ambiguous and frequently misused. Second, the assessment of clinical severity required either the Ranson score or the Acute Physiology and Chronic Health Evaluation II score, both of which are complex and have other limitations. Finally, advances in imaging and treatment have rendered the original Atlanta nomenclature obsolete.

In 2012, the Acute Pancreatitis Classification Working Group issued a revised Atlanta classification that modernized the terminology pertaining to natural history, severity, imaging features, and complications. It divides the natural course of acute pancreatitis into early and late phases.⁴

Early vs late phase

In the early phase, findings on computed tomography (CT) neither correlate with clinical severity nor alter clinical management.⁶ Thus, early imaging is not indicated unless there is diagnostic uncertainty, lack of response to appropriate treatment, or sudden deterioration.

Moderate pancreatitis describes patients with pancreatic necrosis with or without transient organ failure (organ dysfunction for ≤ 48 hours).

Severe pancreatitis is defined by pancreatic necrosis and persistent organ dysfunction.⁴ It may be accompanied by pancreatic and peripancreatic fluid collections; bacteremia and sepsis can occur in association with infection of necrotic collections.

Interstitial edematous pancreatitis vs necrotizing pancreatitis

The revised Atlanta classification maintains the original classification of acute pancreatitis into 2 main categories: interstitial edematous pancreatitis and necrotizing pancreatitis.

Necrotizing pancreatitis is further divided into 3 subtypes based on extent and location of necrosis:

• Parenchymal necrosis alone (5% of cases)
• Necrosis of peripancreatic fat alone (20%)
• Necrosis of both parenchyma and peripancreatic fat (75%).

Peripancreatic involvement is commonly found in the mesentery, peripancreatic and distant retroperitoneum, and lesser sac.

Of the three subtypes, peripancreatic necrosis has the best prognosis. However, all of the subtypes of necrotizing pancreatitis are associated with poorer outcomes than interstitial edematous pancreatitis.

Fluid collections

Acute pancreatic fluid collections contain exclusively nonsolid components without an inflammatory wall and are typically found in the peripancreatic fat. These collections often resolve without intervention as the patient recovers. If they persist beyond 4 weeks and develop a nonepithelialized, fibrous wall, they become pseudocysts. Intervention is generally not recommended for pseudocysts unless they are symptomatic.

Radiographic imaging is not usually necessary to diagnose acute pancreatitis. However, it can be a valuable tool to clarify an ambiguous presentation, determine severity, and identify complications.

The timing and appropriate type of imaging are integral to obtaining useful data. Any imaging obtained in acute pancreatitis to evaluate necrosis should be performed at least 3 to 5 days from the initial symptom onset; if imaging is obtained before 72 hours, necrosis cannot be confidently excluded.⁸

COMPUTED TOMOGRAPHY

CT is the imaging test of choice when evaluating acute pancreatitis. In addition, almost all percutaneous interventions are performed with CT guidance. The Balthazar score is the most well-known CT severity index. It is calculated based on the degree of inflammation, acute fluid collections, and parenchymal necrosis.⁹ However, a modified severity index incorporates extrapancreatic complications such as ascites and vascular compromise and was found to more strongly correlate with outcomes than the standard Balthazar score.¹⁰

Contrast-enhanced CT is performed in 2 phases:

The pancreatic parenchymal phase

The pancreatic parenchymal or late arterial phase is obtained approximately 40 to 45 seconds after the start of the contrast bolus. It is used to detect necrosis in the early phase of acute pancreatitis and to assess the peripancreatic arteries for pseudoaneurysms in the late phase of acute pancreatitis.¹¹

Pancreatic necrosis appears as an area of decreased parenchymal enhancement, either well-defined or heterogeneous. The normal pancreatic parenchyma has a postcontrast enhancement pattern similar to that of the spleen. Parenchyma that does not enhance to the same degree is considered necrotic. The severity of necrosis is graded based on the percentage of the pancreas involved (< 30%, 30%–50%, or > 50%), and a higher percentage correlates with a worse outcome.^12,13

Peripancreatic necrosis is harder to detect, as there is no method to assess fat enhancement as there is with pancreatic parenchymal enhancement. In general, radiologists assume that heterogeneous peripancreatic changes, including areas of fat, fluid, and soft tissue attenuation, are consistent with peripancreatic necrosis. After 7 to 10 days, if these changes become more homogeneous and confluent with a more mass-like process, peripancreatic necrosis can be more confidently identified.^12,13

The portal venous phase

The later, portal venous phase of the scan is obtained approximately 70 seconds after the start of the contrast bolus. It is used to detect and characterize fluid collections and venous complications of the disease.

Drawbacks of CT

A drawback of CT is the need for iodinated intravenous contrast media, which in severely ill patients may precipitate or worsen pre-existing acute kidney injury.

Further, several studies have shown that findings on CT rarely alter the management of patients in the early phase of acute pancreatitis and in fact may be an overuse of medical resources.¹⁴ Unless there are confounding clinical signs or symptoms, CT should be delayed for at least 72 hours.^9,10,14,15

MAGNETIC RESONANCE IMAGING

Magnetic resonance imaging (MRI) is not a first-line imaging test in this disease because it is not as available as CT and takes longer to perform—20 to 30 minutes. The patient must be evaluated for candidacy, as it is difficult for acutely ill patients to tolerate an examination that takes this long and requires them to hold their breath multiple times.

MRI is an appropriate alternative in patients who are pregnant or who have severe iodinated-contrast allergy. While contrast is necessary to detect pancreatic necrosis with CT, MRI can detect necrosis without the need for contrast in patients with acute kidney injury or severe chronic kidney disease. Also, MRI may be better in complicated cases requiring repeated imaging because it does not expose the patient to radiation.

On MRI, pancreatic necrosis appears as a heterogeneous area, owing to its liquid and solid components. Liquid components appear hyperintense, and solid components hypointense, on T2 fluid-weighted imaging. This ability to differentiate the components of a walled-off pancreatic necrosis can be useful in determining whether a collection requires drainage or debridement. MRI is also more sensitive for hemorrhagic complications, best seen on T1 fat-weighted images.^12,16

Magnetic resonance cholangiopancreatography is an excellent method for ductal evaluation through heavily T2-weighted imaging. It is more sensitive than CT for detecting common bile duct stones and can also detect pancreatic duct strictures or extravasation into fluid collections.¹⁶

SUPPORTIVE MANAGEMENT OF EARLY NECROTIZING PANCREATITIS

In the early phase of necrotizing pancreatitis, management is supportive with the primary aim of preventing intravascular volume depletion. Aggressive fluid resuscitation in the first 48 to 72 hours, pain control, and bowel rest are the mainstays of supportive therapy. Intensive care may be necessary if organ failure and hemodynamic instability accompany necrotizing pancreatitis.

Prophylactic antibiotic and antifungal therapy to prevent infected necrosis has been controversial. Recent studies of its utility have not yielded supportive results, and the American College of Gastroenterology and the Infectious Diseases Society of America no longer recommend it.^9,17 These medications should not be given unless concomitant cholangitis or extrapancreatic infection is clinically suspected.

Early enteral nutrition is recommended in patients in whom pancreatitis is predicted to be severe and in those not expected to resume oral intake within 5 to 7 days. Enteral nutrition most commonly involves bedside or endoscopic placement of a nasojejunal feeding tube and collaboration with a nutritionist to determine protein-caloric requirements.

Compared with enteral nutrition, total parenteral nutrition is associated with higher rates of infection, multiorgan dysfunction and failure, and death.¹⁸

Necrotizing pancreatitis is a defining complication of acute pancreatitis, and its presence alone indicates greater severity. However, superimposed complications may further worsen outcomes.

Infected pancreatic necrosis

Infection occurs in approximately 20% of patients with necrotizing pancreatitis and confers a mortality rate of 20% to 50%.¹⁹ Infected pancreatic necrosis occurs when gut organisms translocate into the nearby necrotic pancreatic and peripancreatic tissue. The most commonly identified organisms include Escherichia coli and Enterococcus species.²⁰

This complication usually manifests 2 to 4 weeks after symptom onset; earlier onset is uncommon to rare. It should be considered when the systemic inflammatory response syndrome persists or recurs after 10 days to 2 weeks. Systemic inflammatory response syndrome is also common in sterile necrotizing pancreatitis and sometimes in interstitial pancreatitis, particularly during the first week. However, its sudden appearance or resurgence, high spiking fevers, or worsening organ failure in the later phase (2–4 weeks) of pancreatitis should heighten suspicion of infected pancreatic necrosis.

Imaging may also help diagnose infection, and the presence of gas within a collection or region of necrosis is highly specific. However, the presence of gas is not completely sensitive for infection, as it is seen in only 12% to 22% of infected cases.

Before minimally invasive techniques became available, the diagnosis of infected pancreatic necrosis was confirmed by percutaneous CT-guided aspiration of the necrotic mass or collection for Gram stain and culture.

Antibiotic therapy is indicated in confirmed or suspected cases of infected pancreatic necrosis. Antibiotics with gram-negative coverage and appropriate penetration such as carbapenems, metronidazole, fluoroquinolones, and selected cephalosporins are most commonly used. Meropenem is the antibiotic of choice at our institution.

CT-guided fine-needle aspiration is often done if suspected infected pancreatic necrosis fails to respond to empiric antibiotic therapy.

Debridement or drainage. Generally, the diagnosis or suspicion of infected pancreatic necrosis (suggestive signs are high fever, elevated white blood cell count, and sepsis) warrants an intervention to debride or drain infected pancreatic tissue and control sepsis.²¹

While source control is integral to the successful treatment of infected pancreatic necrosis, antibiotic therapy may provide a bridge to intervention for critically ill patients by suppressing bacteremia and subsequent sepsis. A 2013 meta-analysis found that 324 of 409 patients with suspected infected pancreatic necrosis were successfully stabilized with antibiotic treatment.^21,22 The trend toward conservative management and promising outcomes with antibiotic therapy alone or with minimally invasive techniques has lessened the need for diagnostic CT-guided fine-needle aspiration.

Hemorrhage

Spontaneous hemorrhage into pancreatic necrosis is a rare but life-threatening complication. Because CT is almost always performed with contrast enhancement, this complication is rarely identified with imaging. The diagnosis is made by noting a drop in hemoglobin and hematocrit.

Hemorrhage into the retroperitoneum or the peritoneal cavity, or both, can occur when an inflammatory process erodes into a nearby artery. Luminal gastrointestinal bleeding can occur from gastric varices arising from splenic vein thrombosis and resulting left-sided portal hypertension, or from pseudoaneurysms. These can also bleed into the pancreatic duct (hemosuccus pancreaticus). Pseudoaneurysm is a later complication that occurs when an arterial wall (most commonly the splenic or gastroduodenal artery) is weakened by pancreatic enzymes.²³

Prompt recognition of hemorrhagic events and consultation with an interventional radiologist or surgeon are required to prevent death.

Inflammation and abdominal compartment syndrome

Inflammation from necrotizing pancreatitis can cause further complications by blocking nearby structures. Reported complications include jaundice from biliary compression, hydronephrosis from ureteral compression, bowel obstruction, and gastric outlet obstruction.

Abdominal compartment syndrome is an increasingly recognized complication of acute pancreatitis. Abdominal pressure can rise due to a number of factors, including fluid collections, ascites, ileus, and overly aggressive fluid resuscitation.²⁴ Elevated abdominal pressure is associated with complications such as decreased respiratory compliance, increased peak airway pressure, decreased cardiac preload, hypotension, mesenteric and intestinal ischemia, feeding intolerance, and lower-extremity ischemia and thrombosis.

Patients with necrotizing pancreatitis who have abdominal compartment syndrome have a mortality rate 5 times higher than patients without abdominal compartment syndrome.²⁵

Abdominal pressures should be monitored using a bladder pressure sensor in critically ill or ventilated patients with acute pancreatitis. If the abdominal pressure rises above 20 mm Hg, medical and surgical interventions should be offered in a stepwise fashion to decrease it. Interventions include decompression by nasogastric and rectal tube, sedation or paralysis to relax abdominal wall tension, minimization of intravenous fluids, percutaneous drainage of ascites, and (rarely) surgical midline or subcostal laparotomy.

The treatment of necrotizing pancreatitis has changed rapidly, thanks to a growing experience with minimally invasive techniques.

Indications for intervention

Infected pancreatic necrosis is the primary indication for surgical, percutaneous, or endoscopic intervention.

In sterile necrosis, the threshold for intervention is less clear, and intervention is often reserved for patients who fail to clinically improve or who have intractable abdominal pain, gastric outlet obstruction, or fistulating disease.²⁶

In asymptomatic cases, intervention is almost never indicated regardless of the location or size of the necrotic area.

In walled-off pancreatic necrosis, less-invasive and less-morbid interventions such as endoscopic or percutaneous drainage or video-assisted retroperitoneal debridement can be done.

Timing of intervention

In the past, delaying intervention was thought to increase the risk of death. However, multiple studies have found that outcomes are often worse if intervention is done early, likely due to the lack of a fully formed fibrous wall or demarcation of the necrotic area.²⁷

If the patient remains clinically stable, it is best to delay intervention until at least 4 weeks after the index event to achieve optimal outcomes. Delay can often be achieved by antibiotic treatment to suppress bacteremia and endoscopic or percutaneous drainage of infected collections to control sepsis.

Open surgery

The gold-standard intervention for infected pancreatic necrosis or symptomatic sterile walled-off pancreatic necrosis is open necrosectomy. This involves exploratory laparotomy with blunt debridement of all visible necrotic pancreatic tissue.

Methods to facilitate later evacuation of residual infected fluid and debris vary widely. Multiple large-caliber drains can be placed to facilitate irrigation and drainage before closure of the abdominal fascia. As infected pancreatic necrosis carries the risk of contaminating the peritoneal cavity, the skin is often left open to heal by secondary intention. An interventional radiologist is frequently enlisted to place, exchange, or downsize drainage catheters.

Infected pancreatic necrosis or symptomatic sterile walled-off pancreatic necrosis often requires more than one operation to achieve satisfactory debridement.

The goals of open necrosectomy are to remove nonviable tissue and infection, preserve viable pancreatic tissue, eliminate fistulous connections, and minimize damage to local organs and vasculature.

Minimally invasive techniques

Video-assisted retroperitoneal debridement has been described as a hybrid between endoscopic and open retroperitoneal debridement.²⁸ This technique requires first placing a percutaneous catheter into the necrotic area through the left flank to create a retroperitoneal tract. A 5-cm incision is made and the necrotic space is entered using the drain for guidance. Necrotic tissue is carefully debrided under direct vision using a combination of forceps, irrigation, and suction. A laparoscopic port can also be introduced into the incision when the procedure can no longer be continued under direct vision.^29,30

Although not all patients are candidates for minimal-access surgery, it remains an evolving surgical option.

Endoscopic transmural debridement is another option for infected pancreatic necrosis and symptomatic walled-off pancreatic necrosis. Depending on the location of the necrotic area, an echoendoscope is passed to either the stomach or duodenum. Guided by endoscopic ultrasonography, a needle is passed into the collection, allowing subsequent fistula creation and stenting for internal drainage or debridement. In the past, this process required several steps, multiple devices, fluoroscopic guidance, and considerable time. But newer endoscopic lumen-apposing metal stents have been developed that can be placed in a single step without fluoroscopy. A slimmer endoscope can then be introduced into the necrotic cavity via the stent, and the necrotic debris can be debrided with endoscopic baskets, snares, forceps, and irrigation.^9,31

Similar to surgical necrosectomy, satisfactory debridement is not often obtained with a single procedure; 2 to 5 endoscopic procedures may be needed to achieve resolution. However, the luminal approach in endoscopic necrosectomy avoids the significant morbidity of major abdominal surgery and the potential for pancreaticocutaneous fistulae that may occur with drains.

In a randomized trial comparing endoscopic necrosectomy vs surgical necrosectomy (video-assisted retroperitoneal debridement and exploratory laparotomy),³² endoscopic necrosectomy showed less inflammatory response than surgical necrosectomy and had a lower risk of new-onset organ failure, bleeding, fistula formation, and death.³²

Selecting the best intervention for the individual patient

Given the multiple available techniques, selecting the best intervention for individual patients can be challenging. A team approach with input from a gastroenterologist, surgeon, and interventional radiologist is best when determining which technique would best suit each patient.

Surgical necrosectomy is still the treatment of choice for unstable patients with infected pancreatic necrosis or multiple, inaccessible collections, but current evidence suggests a different approach in stable infected pancreatic necrosis and symptomatic sterile walled-off pancreatic necrosis.

The Dutch Pancreatitis Group²⁸ randomized 88 patients with infected pancreatic necrosis or symptomatic walled-off pancreatic necrosis to open necrosectomy or a minimally invasive “step-up” approach consisting of up to 2 percutaneous drainage or endoscopic debridement procedures before escalation to video-assisted retroperitoneal debridement. The step-up approach resulted in lower rates of morbidity and death than surgical necrosectomy as first-line treatment. Furthermore, some patients in the step-up group avoided the need for surgery entirely.³⁰

Necrosis significantly increases rates of morbidity and mortality in acute pancreatitis. Hospitalists, general internists, and general surgeons are all on the front lines in identifying severe cases and consulting the appropriate specialists for optimal multidisciplinary care. Selective and appropriate timing of radiologic imaging is key, and a vital tool in the management of necrotizing pancreatitis.

While the primary indication for intervention is infected pancreatic necrosis, additional indications are symptomatic walled-off pancreatic necrosis secondary to intractable abdominal pain, bowel obstruction, and failure to thrive. As a result of improving technology and inpatient care, these patients may present with intractable symptoms in the outpatient setting rather than the inpatient setting. The onus is on the primary care physician to maintain a high level of suspicion and refer these patients to subspecialists as appropriate.

Open surgical necrosectomy remains an important approach for care of infected pancreatic necrosis or patients with intractable symptoms. A step-up approach starting with a minimally invasive procedure and escalating if the initial intervention is unsuccessful is gradually becoming the standard of care.

Acute pancreatitis accounted for more than 300,000 admissions and $2.6 billion in associated healthcare costs in the United States in 2012.¹ First-line management is early aggressive fluid resuscitation and analgesics for pain control. Guidelines recommend estimating the clinical severity of each attack using a validated scoring system such as the Bedside Index of Severity in Acute Pancreatitis.² Clinically severe pancreatitis is associated with necrosis.

Acute pancreatitis results from inappropriate activation of zymogens and subsequent auto­digestion of the pancreas by its own enzymes. Though necrotizing pancreatitis is thought to be an ischemic complication, its pathogenesis is not completely understood. Necrosis increases the morbidity and mortality risk of acute pancreatitis because of its association with organ failure and infectious complications. As such, patients with necrotizing pancreatitis may need admission to the intensive care unit, nutritional support, antibiotics, and radiologic, endoscopic, or surgical interventions.

Here, we review current evidence regarding the diagnosis and management of necrotizing pancreatitis.

PROPER TERMINOLOGY HELPS COLLABORATION

Managing necrotizing pancreatitis requires the combined efforts of internists, gastroenterologists, radiologists, and surgeons. This collaboration is aided by proper terminology.

A classification system was devised in Atlanta, GA, in 1992 to facilitate communication and interdisciplinary collaboration.³ Severe pancreatitis was differentiated from mild by the presence of organ failure or the complications of pseudocyst, necrosis, or abscess.

The original Atlanta classification had several limitations. First, the terminology for fluid collections was ambiguous and frequently misused. Second, the assessment of clinical severity required either the Ranson score or the Acute Physiology and Chronic Health Evaluation II score, both of which are complex and have other limitations. Finally, advances in imaging and treatment have rendered the original Atlanta nomenclature obsolete.

In 2012, the Acute Pancreatitis Classification Working Group issued a revised Atlanta classification that modernized the terminology pertaining to natural history, severity, imaging features, and complications. It divides the natural course of acute pancreatitis into early and late phases.⁴

Early vs late phase

In the early phase, findings on computed tomography (CT) neither correlate with clinical severity nor alter clinical management.⁶ Thus, early imaging is not indicated unless there is diagnostic uncertainty, lack of response to appropriate treatment, or sudden deterioration.

Moderate pancreatitis describes patients with pancreatic necrosis with or without transient organ failure (organ dysfunction for ≤ 48 hours).

Severe pancreatitis is defined by pancreatic necrosis and persistent organ dysfunction.⁴ It may be accompanied by pancreatic and peripancreatic fluid collections; bacteremia and sepsis can occur in association with infection of necrotic collections.

Interstitial edematous pancreatitis vs necrotizing pancreatitis

The revised Atlanta classification maintains the original classification of acute pancreatitis into 2 main categories: interstitial edematous pancreatitis and necrotizing pancreatitis.

Necrotizing pancreatitis is further divided into 3 subtypes based on extent and location of necrosis:

• Parenchymal necrosis alone (5% of cases)
• Necrosis of peripancreatic fat alone (20%)
• Necrosis of both parenchyma and peripancreatic fat (75%).

Peripancreatic involvement is commonly found in the mesentery, peripancreatic and distant retroperitoneum, and lesser sac.

Of the three subtypes, peripancreatic necrosis has the best prognosis. However, all of the subtypes of necrotizing pancreatitis are associated with poorer outcomes than interstitial edematous pancreatitis.

Fluid collections

Acute pancreatic fluid collections contain exclusively nonsolid components without an inflammatory wall and are typically found in the peripancreatic fat. These collections often resolve without intervention as the patient recovers. If they persist beyond 4 weeks and develop a nonepithelialized, fibrous wall, they become pseudocysts. Intervention is generally not recommended for pseudocysts unless they are symptomatic.

Radiographic imaging is not usually necessary to diagnose acute pancreatitis. However, it can be a valuable tool to clarify an ambiguous presentation, determine severity, and identify complications.

The timing and appropriate type of imaging are integral to obtaining useful data. Any imaging obtained in acute pancreatitis to evaluate necrosis should be performed at least 3 to 5 days from the initial symptom onset; if imaging is obtained before 72 hours, necrosis cannot be confidently excluded.⁸

COMPUTED TOMOGRAPHY

CT is the imaging test of choice when evaluating acute pancreatitis. In addition, almost all percutaneous interventions are performed with CT guidance. The Balthazar score is the most well-known CT severity index. It is calculated based on the degree of inflammation, acute fluid collections, and parenchymal necrosis.⁹ However, a modified severity index incorporates extrapancreatic complications such as ascites and vascular compromise and was found to more strongly correlate with outcomes than the standard Balthazar score.¹⁰

Contrast-enhanced CT is performed in 2 phases:

The pancreatic parenchymal phase

The pancreatic parenchymal or late arterial phase is obtained approximately 40 to 45 seconds after the start of the contrast bolus. It is used to detect necrosis in the early phase of acute pancreatitis and to assess the peripancreatic arteries for pseudoaneurysms in the late phase of acute pancreatitis.¹¹

Pancreatic necrosis appears as an area of decreased parenchymal enhancement, either well-defined or heterogeneous. The normal pancreatic parenchyma has a postcontrast enhancement pattern similar to that of the spleen. Parenchyma that does not enhance to the same degree is considered necrotic. The severity of necrosis is graded based on the percentage of the pancreas involved (< 30%, 30%–50%, or > 50%), and a higher percentage correlates with a worse outcome.^12,13

Peripancreatic necrosis is harder to detect, as there is no method to assess fat enhancement as there is with pancreatic parenchymal enhancement. In general, radiologists assume that heterogeneous peripancreatic changes, including areas of fat, fluid, and soft tissue attenuation, are consistent with peripancreatic necrosis. After 7 to 10 days, if these changes become more homogeneous and confluent with a more mass-like process, peripancreatic necrosis can be more confidently identified.^12,13

The portal venous phase

The later, portal venous phase of the scan is obtained approximately 70 seconds after the start of the contrast bolus. It is used to detect and characterize fluid collections and venous complications of the disease.

Drawbacks of CT

A drawback of CT is the need for iodinated intravenous contrast media, which in severely ill patients may precipitate or worsen pre-existing acute kidney injury.

Further, several studies have shown that findings on CT rarely alter the management of patients in the early phase of acute pancreatitis and in fact may be an overuse of medical resources.¹⁴ Unless there are confounding clinical signs or symptoms, CT should be delayed for at least 72 hours.^9,10,14,15

MAGNETIC RESONANCE IMAGING

Magnetic resonance imaging (MRI) is not a first-line imaging test in this disease because it is not as available as CT and takes longer to perform—20 to 30 minutes. The patient must be evaluated for candidacy, as it is difficult for acutely ill patients to tolerate an examination that takes this long and requires them to hold their breath multiple times.

MRI is an appropriate alternative in patients who are pregnant or who have severe iodinated-contrast allergy. While contrast is necessary to detect pancreatic necrosis with CT, MRI can detect necrosis without the need for contrast in patients with acute kidney injury or severe chronic kidney disease. Also, MRI may be better in complicated cases requiring repeated imaging because it does not expose the patient to radiation.

On MRI, pancreatic necrosis appears as a heterogeneous area, owing to its liquid and solid components. Liquid components appear hyperintense, and solid components hypointense, on T2 fluid-weighted imaging. This ability to differentiate the components of a walled-off pancreatic necrosis can be useful in determining whether a collection requires drainage or debridement. MRI is also more sensitive for hemorrhagic complications, best seen on T1 fat-weighted images.^12,16

Magnetic resonance cholangiopancreatography is an excellent method for ductal evaluation through heavily T2-weighted imaging. It is more sensitive than CT for detecting common bile duct stones and can also detect pancreatic duct strictures or extravasation into fluid collections.¹⁶

SUPPORTIVE MANAGEMENT OF EARLY NECROTIZING PANCREATITIS

In the early phase of necrotizing pancreatitis, management is supportive with the primary aim of preventing intravascular volume depletion. Aggressive fluid resuscitation in the first 48 to 72 hours, pain control, and bowel rest are the mainstays of supportive therapy. Intensive care may be necessary if organ failure and hemodynamic instability accompany necrotizing pancreatitis.

Prophylactic antibiotic and antifungal therapy to prevent infected necrosis has been controversial. Recent studies of its utility have not yielded supportive results, and the American College of Gastroenterology and the Infectious Diseases Society of America no longer recommend it.^9,17 These medications should not be given unless concomitant cholangitis or extrapancreatic infection is clinically suspected.

Early enteral nutrition is recommended in patients in whom pancreatitis is predicted to be severe and in those not expected to resume oral intake within 5 to 7 days. Enteral nutrition most commonly involves bedside or endoscopic placement of a nasojejunal feeding tube and collaboration with a nutritionist to determine protein-caloric requirements.

Compared with enteral nutrition, total parenteral nutrition is associated with higher rates of infection, multiorgan dysfunction and failure, and death.¹⁸

Necrotizing pancreatitis is a defining complication of acute pancreatitis, and its presence alone indicates greater severity. However, superimposed complications may further worsen outcomes.

Infected pancreatic necrosis

Infection occurs in approximately 20% of patients with necrotizing pancreatitis and confers a mortality rate of 20% to 50%.¹⁹ Infected pancreatic necrosis occurs when gut organisms translocate into the nearby necrotic pancreatic and peripancreatic tissue. The most commonly identified organisms include Escherichia coli and Enterococcus species.²⁰

This complication usually manifests 2 to 4 weeks after symptom onset; earlier onset is uncommon to rare. It should be considered when the systemic inflammatory response syndrome persists or recurs after 10 days to 2 weeks. Systemic inflammatory response syndrome is also common in sterile necrotizing pancreatitis and sometimes in interstitial pancreatitis, particularly during the first week. However, its sudden appearance or resurgence, high spiking fevers, or worsening organ failure in the later phase (2–4 weeks) of pancreatitis should heighten suspicion of infected pancreatic necrosis.

Imaging may also help diagnose infection, and the presence of gas within a collection or region of necrosis is highly specific. However, the presence of gas is not completely sensitive for infection, as it is seen in only 12% to 22% of infected cases.

Before minimally invasive techniques became available, the diagnosis of infected pancreatic necrosis was confirmed by percutaneous CT-guided aspiration of the necrotic mass or collection for Gram stain and culture.

Antibiotic therapy is indicated in confirmed or suspected cases of infected pancreatic necrosis. Antibiotics with gram-negative coverage and appropriate penetration such as carbapenems, metronidazole, fluoroquinolones, and selected cephalosporins are most commonly used. Meropenem is the antibiotic of choice at our institution.

CT-guided fine-needle aspiration is often done if suspected infected pancreatic necrosis fails to respond to empiric antibiotic therapy.

Debridement or drainage. Generally, the diagnosis or suspicion of infected pancreatic necrosis (suggestive signs are high fever, elevated white blood cell count, and sepsis) warrants an intervention to debride or drain infected pancreatic tissue and control sepsis.²¹

While source control is integral to the successful treatment of infected pancreatic necrosis, antibiotic therapy may provide a bridge to intervention for critically ill patients by suppressing bacteremia and subsequent sepsis. A 2013 meta-analysis found that 324 of 409 patients with suspected infected pancreatic necrosis were successfully stabilized with antibiotic treatment.^21,22 The trend toward conservative management and promising outcomes with antibiotic therapy alone or with minimally invasive techniques has lessened the need for diagnostic CT-guided fine-needle aspiration.

Hemorrhage

Spontaneous hemorrhage into pancreatic necrosis is a rare but life-threatening complication. Because CT is almost always performed with contrast enhancement, this complication is rarely identified with imaging. The diagnosis is made by noting a drop in hemoglobin and hematocrit.

Hemorrhage into the retroperitoneum or the peritoneal cavity, or both, can occur when an inflammatory process erodes into a nearby artery. Luminal gastrointestinal bleeding can occur from gastric varices arising from splenic vein thrombosis and resulting left-sided portal hypertension, or from pseudoaneurysms. These can also bleed into the pancreatic duct (hemosuccus pancreaticus). Pseudoaneurysm is a later complication that occurs when an arterial wall (most commonly the splenic or gastroduodenal artery) is weakened by pancreatic enzymes.²³

Prompt recognition of hemorrhagic events and consultation with an interventional radiologist or surgeon are required to prevent death.

Inflammation and abdominal compartment syndrome

Inflammation from necrotizing pancreatitis can cause further complications by blocking nearby structures. Reported complications include jaundice from biliary compression, hydronephrosis from ureteral compression, bowel obstruction, and gastric outlet obstruction.

Abdominal compartment syndrome is an increasingly recognized complication of acute pancreatitis. Abdominal pressure can rise due to a number of factors, including fluid collections, ascites, ileus, and overly aggressive fluid resuscitation.²⁴ Elevated abdominal pressure is associated with complications such as decreased respiratory compliance, increased peak airway pressure, decreased cardiac preload, hypotension, mesenteric and intestinal ischemia, feeding intolerance, and lower-extremity ischemia and thrombosis.

Patients with necrotizing pancreatitis who have abdominal compartment syndrome have a mortality rate 5 times higher than patients without abdominal compartment syndrome.²⁵

Abdominal pressures should be monitored using a bladder pressure sensor in critically ill or ventilated patients with acute pancreatitis. If the abdominal pressure rises above 20 mm Hg, medical and surgical interventions should be offered in a stepwise fashion to decrease it. Interventions include decompression by nasogastric and rectal tube, sedation or paralysis to relax abdominal wall tension, minimization of intravenous fluids, percutaneous drainage of ascites, and (rarely) surgical midline or subcostal laparotomy.

The treatment of necrotizing pancreatitis has changed rapidly, thanks to a growing experience with minimally invasive techniques.

Indications for intervention

Infected pancreatic necrosis is the primary indication for surgical, percutaneous, or endoscopic intervention.

In sterile necrosis, the threshold for intervention is less clear, and intervention is often reserved for patients who fail to clinically improve or who have intractable abdominal pain, gastric outlet obstruction, or fistulating disease.²⁶

In asymptomatic cases, intervention is almost never indicated regardless of the location or size of the necrotic area.

In walled-off pancreatic necrosis, less-invasive and less-morbid interventions such as endoscopic or percutaneous drainage or video-assisted retroperitoneal debridement can be done.

Timing of intervention

In the past, delaying intervention was thought to increase the risk of death. However, multiple studies have found that outcomes are often worse if intervention is done early, likely due to the lack of a fully formed fibrous wall or demarcation of the necrotic area.²⁷

If the patient remains clinically stable, it is best to delay intervention until at least 4 weeks after the index event to achieve optimal outcomes. Delay can often be achieved by antibiotic treatment to suppress bacteremia and endoscopic or percutaneous drainage of infected collections to control sepsis.

Open surgery

The gold-standard intervention for infected pancreatic necrosis or symptomatic sterile walled-off pancreatic necrosis is open necrosectomy. This involves exploratory laparotomy with blunt debridement of all visible necrotic pancreatic tissue.

Methods to facilitate later evacuation of residual infected fluid and debris vary widely. Multiple large-caliber drains can be placed to facilitate irrigation and drainage before closure of the abdominal fascia. As infected pancreatic necrosis carries the risk of contaminating the peritoneal cavity, the skin is often left open to heal by secondary intention. An interventional radiologist is frequently enlisted to place, exchange, or downsize drainage catheters.

Infected pancreatic necrosis or symptomatic sterile walled-off pancreatic necrosis often requires more than one operation to achieve satisfactory debridement.

The goals of open necrosectomy are to remove nonviable tissue and infection, preserve viable pancreatic tissue, eliminate fistulous connections, and minimize damage to local organs and vasculature.

Minimally invasive techniques

Video-assisted retroperitoneal debridement has been described as a hybrid between endoscopic and open retroperitoneal debridement.²⁸ This technique requires first placing a percutaneous catheter into the necrotic area through the left flank to create a retroperitoneal tract. A 5-cm incision is made and the necrotic space is entered using the drain for guidance. Necrotic tissue is carefully debrided under direct vision using a combination of forceps, irrigation, and suction. A laparoscopic port can also be introduced into the incision when the procedure can no longer be continued under direct vision.^29,30

Although not all patients are candidates for minimal-access surgery, it remains an evolving surgical option.

Endoscopic transmural debridement is another option for infected pancreatic necrosis and symptomatic walled-off pancreatic necrosis. Depending on the location of the necrotic area, an echoendoscope is passed to either the stomach or duodenum. Guided by endoscopic ultrasonography, a needle is passed into the collection, allowing subsequent fistula creation and stenting for internal drainage or debridement. In the past, this process required several steps, multiple devices, fluoroscopic guidance, and considerable time. But newer endoscopic lumen-apposing metal stents have been developed that can be placed in a single step without fluoroscopy. A slimmer endoscope can then be introduced into the necrotic cavity via the stent, and the necrotic debris can be debrided with endoscopic baskets, snares, forceps, and irrigation.^9,31

Similar to surgical necrosectomy, satisfactory debridement is not often obtained with a single procedure; 2 to 5 endoscopic procedures may be needed to achieve resolution. However, the luminal approach in endoscopic necrosectomy avoids the significant morbidity of major abdominal surgery and the potential for pancreaticocutaneous fistulae that may occur with drains.

In a randomized trial comparing endoscopic necrosectomy vs surgical necrosectomy (video-assisted retroperitoneal debridement and exploratory laparotomy),³² endoscopic necrosectomy showed less inflammatory response than surgical necrosectomy and had a lower risk of new-onset organ failure, bleeding, fistula formation, and death.³²

Selecting the best intervention for the individual patient

Given the multiple available techniques, selecting the best intervention for individual patients can be challenging. A team approach with input from a gastroenterologist, surgeon, and interventional radiologist is best when determining which technique would best suit each patient.

Surgical necrosectomy is still the treatment of choice for unstable patients with infected pancreatic necrosis or multiple, inaccessible collections, but current evidence suggests a different approach in stable infected pancreatic necrosis and symptomatic sterile walled-off pancreatic necrosis.

The Dutch Pancreatitis Group²⁸ randomized 88 patients with infected pancreatic necrosis or symptomatic walled-off pancreatic necrosis to open necrosectomy or a minimally invasive “step-up” approach consisting of up to 2 percutaneous drainage or endoscopic debridement procedures before escalation to video-assisted retroperitoneal debridement. The step-up approach resulted in lower rates of morbidity and death than surgical necrosectomy as first-line treatment. Furthermore, some patients in the step-up group avoided the need for surgery entirely.³⁰

Necrosis significantly increases rates of morbidity and mortality in acute pancreatitis. Hospitalists, general internists, and general surgeons are all on the front lines in identifying severe cases and consulting the appropriate specialists for optimal multidisciplinary care. Selective and appropriate timing of radiologic imaging is key, and a vital tool in the management of necrotizing pancreatitis.

While the primary indication for intervention is infected pancreatic necrosis, additional indications are symptomatic walled-off pancreatic necrosis secondary to intractable abdominal pain, bowel obstruction, and failure to thrive. As a result of improving technology and inpatient care, these patients may present with intractable symptoms in the outpatient setting rather than the inpatient setting. The onus is on the primary care physician to maintain a high level of suspicion and refer these patients to subspecialists as appropriate.

Open surgical necrosectomy remains an important approach for care of infected pancreatic necrosis or patients with intractable symptoms. A step-up approach starting with a minimally invasive procedure and escalating if the initial intervention is unsuccessful is gradually becoming the standard of care.

Some of you who are reading this column likely are military brats from one branch or another. Many of us felt the call to give back by either joining the military, PHS, or working in organizations like the VA, treating former service members. That certainly was a huge motivation for me to become a VA physician. I always felt more welcomed, even felt at home, at the VA or at a military hospital than I did at any civilian health care facility. And many of my colleagues feel the same way. Other brats have never interacted much with the military except for their being raised by family members in the armed forces; yet this designation is still a part of their identity, one that is especially important as the number of Americans with a military connection continues to decline.

The percentage of adults > 50 years old who have an immediate family member who served in the military is 77%; the percentage of those aged 30 to 49 years is 57%; and aged < 30 years, only 33%.¹ Almost 5% of adult Americans are military brats. This demographic trend brings with it an increasing chance that current and former service members may feel socially isolated and that many health care professionals will struggle to relate to, and appreciate, their unique cultural background.

Authors always should acknowledge any material conflict of interest, and as a double Army brat, I am far from objective on this subject. I was born and raised on an army base. My father was a career military physician, and my mother, albeit briefly, was an army nurse. Some of my earliest memories are of being with my father and driving around Fort Sam Houston when everyone and everything stopped upon hearing the sound of a bugle (at the time, it was still a real bugle). My father and I would get out of the car. He would salute, and I would stand as still as a small active child can while we turned toward the flag being lowered over the base.

In reading about army brats, this memory seems to be a common one. Many individuals have commented on how this repeated experience from their youth instilled in them a sense of respect for our flag and country and an appreciation of order and discipline that stayed with them long after they became adults.

Obviously, while those of us claiming this identity use it positively as a phrase of winsome nostalgia and civic pride, in everyday language a brat is a pejorative reference. The online magazine Military Brat Life, defines the term as “someone, who, as a child, grows up in a family where one or more parents are ‘career’ military, and where the children move from base to base, experiencing life in several different places and possibly different countries.”² The phrase denotes an individual whose parents at some point served full-time in the military, no duration is specified or whether the parents had to be active duty, reserve or National Guard members. The prefix for the label comes from the military branch in which the parents primarily served, though like hyphenated names some younger generations will introduce themselves as a Navy-Air Force brat. Other sites suggest that it doesn’t refer to a spoiled child at all but actually is yet another of the acronyms that proliferate in military environments. Although after I read these possible theories, many seemed retrospective attempts to jettison the negative connotations.

I learned that like others sharing similar formative experiences, military brats are considered a subculture or a third culture, in some of the literature. There is a dearth of scholarly data about the phenomenology and social psychology of adults who spent some of their formative years under the auspices of military culture. As in any foray into cultural competence, avoiding stereotypes is crucial. However, research has shown that the experience of growing up in the military is one that bestows resilience and risk.³ It is also an important piece of a patient’s narrative that health care professionals in and out of the federal system should consider to provide patient-centered care.

A childhood in a military environment is often romanticized as shaping an adult who is worldly, cosmopolitan, resilient, and tolerant. Although these are adaptive traits that children of military personnel develop, there also is a far darker side emerging in the research.⁴ We are all too aware of the epidemic of suicide, opioid use, and posttraumatic stress disorder that has developed in the wake of our country’s latest and lasting conflicts. The reverberations of these mental health problems are felt by the children who lived through them or who lost loved ones to war or suicide. The DoD has begun recognizing this collateral damage and is developing innovative programs to help children and adolescents.

We need to do more though, not just in this arena when the wounds occur, but also later when those wounded come to nurse practitioners and psychologists, social workers, and physicians. Our growing number of community partners through Choice and other programs also need to be aware of the potential mental health impacts of being a military brat or family member.

In the introduction to one of the best books written on the subject, Military Brats: Legacies of Childhood Inside the Fortress, author Pat Conroy wrote, “I thought I was singular in all this, one of a kind.... I discovered that I speak in the multitongued, deep-throated voice of my tribe. It’s a language I was not even aware I spoke... a secret family I did not know I had.... Military brats, my lost tribe, spent their entire youth in service to this country, and no one even knew we were there.”⁵

Some of you who are reading this column likely are military brats from one branch or another. Many of us felt the call to give back by either joining the military, PHS, or working in organizations like the VA, treating former service members. That certainly was a huge motivation for me to become a VA physician. I always felt more welcomed, even felt at home, at the VA or at a military hospital than I did at any civilian health care facility. And many of my colleagues feel the same way. Other brats have never interacted much with the military except for their being raised by family members in the armed forces; yet this designation is still a part of their identity, one that is especially important as the number of Americans with a military connection continues to decline.

The percentage of adults > 50 years old who have an immediate family member who served in the military is 77%; the percentage of those aged 30 to 49 years is 57%; and aged < 30 years, only 33%.¹ Almost 5% of adult Americans are military brats. This demographic trend brings with it an increasing chance that current and former service members may feel socially isolated and that many health care professionals will struggle to relate to, and appreciate, their unique cultural background.

Authors always should acknowledge any material conflict of interest, and as a double Army brat, I am far from objective on this subject. I was born and raised on an army base. My father was a career military physician, and my mother, albeit briefly, was an army nurse. Some of my earliest memories are of being with my father and driving around Fort Sam Houston when everyone and everything stopped upon hearing the sound of a bugle (at the time, it was still a real bugle). My father and I would get out of the car. He would salute, and I would stand as still as a small active child can while we turned toward the flag being lowered over the base.

In reading about army brats, this memory seems to be a common one. Many individuals have commented on how this repeated experience from their youth instilled in them a sense of respect for our flag and country and an appreciation of order and discipline that stayed with them long after they became adults.

Obviously, while those of us claiming this identity use it positively as a phrase of winsome nostalgia and civic pride, in everyday language a brat is a pejorative reference. The online magazine Military Brat Life, defines the term as “someone, who, as a child, grows up in a family where one or more parents are ‘career’ military, and where the children move from base to base, experiencing life in several different places and possibly different countries.”² The phrase denotes an individual whose parents at some point served full-time in the military, no duration is specified or whether the parents had to be active duty, reserve or National Guard members. The prefix for the label comes from the military branch in which the parents primarily served, though like hyphenated names some younger generations will introduce themselves as a Navy-Air Force brat. Other sites suggest that it doesn’t refer to a spoiled child at all but actually is yet another of the acronyms that proliferate in military environments. Although after I read these possible theories, many seemed retrospective attempts to jettison the negative connotations.

I learned that like others sharing similar formative experiences, military brats are considered a subculture or a third culture, in some of the literature. There is a dearth of scholarly data about the phenomenology and social psychology of adults who spent some of their formative years under the auspices of military culture. As in any foray into cultural competence, avoiding stereotypes is crucial. However, research has shown that the experience of growing up in the military is one that bestows resilience and risk.³ It is also an important piece of a patient’s narrative that health care professionals in and out of the federal system should consider to provide patient-centered care.

A childhood in a military environment is often romanticized as shaping an adult who is worldly, cosmopolitan, resilient, and tolerant. Although these are adaptive traits that children of military personnel develop, there also is a far darker side emerging in the research.⁴ We are all too aware of the epidemic of suicide, opioid use, and posttraumatic stress disorder that has developed in the wake of our country’s latest and lasting conflicts. The reverberations of these mental health problems are felt by the children who lived through them or who lost loved ones to war or suicide. The DoD has begun recognizing this collateral damage and is developing innovative programs to help children and adolescents.

We need to do more though, not just in this arena when the wounds occur, but also later when those wounded come to nurse practitioners and psychologists, social workers, and physicians. Our growing number of community partners through Choice and other programs also need to be aware of the potential mental health impacts of being a military brat or family member.

In the introduction to one of the best books written on the subject, Military Brats: Legacies of Childhood Inside the Fortress, author Pat Conroy wrote, “I thought I was singular in all this, one of a kind.... I discovered that I speak in the multitongued, deep-throated voice of my tribe. It’s a language I was not even aware I spoke... a secret family I did not know I had.... Military brats, my lost tribe, spent their entire youth in service to this country, and no one even knew we were there.”⁵

Some of you who are reading this column likely are military brats from one branch or another. Many of us felt the call to give back by either joining the military, PHS, or working in organizations like the VA, treating former service members. That certainly was a huge motivation for me to become a VA physician. I always felt more welcomed, even felt at home, at the VA or at a military hospital than I did at any civilian health care facility. And many of my colleagues feel the same way. Other brats have never interacted much with the military except for their being raised by family members in the armed forces; yet this designation is still a part of their identity, one that is especially important as the number of Americans with a military connection continues to decline.

The percentage of adults > 50 years old who have an immediate family member who served in the military is 77%; the percentage of those aged 30 to 49 years is 57%; and aged < 30 years, only 33%.¹ Almost 5% of adult Americans are military brats. This demographic trend brings with it an increasing chance that current and former service members may feel socially isolated and that many health care professionals will struggle to relate to, and appreciate, their unique cultural background.

Authors always should acknowledge any material conflict of interest, and as a double Army brat, I am far from objective on this subject. I was born and raised on an army base. My father was a career military physician, and my mother, albeit briefly, was an army nurse. Some of my earliest memories are of being with my father and driving around Fort Sam Houston when everyone and everything stopped upon hearing the sound of a bugle (at the time, it was still a real bugle). My father and I would get out of the car. He would salute, and I would stand as still as a small active child can while we turned toward the flag being lowered over the base.

In reading about army brats, this memory seems to be a common one. Many individuals have commented on how this repeated experience from their youth instilled in them a sense of respect for our flag and country and an appreciation of order and discipline that stayed with them long after they became adults.

Obviously, while those of us claiming this identity use it positively as a phrase of winsome nostalgia and civic pride, in everyday language a brat is a pejorative reference. The online magazine Military Brat Life, defines the term as “someone, who, as a child, grows up in a family where one or more parents are ‘career’ military, and where the children move from base to base, experiencing life in several different places and possibly different countries.”² The phrase denotes an individual whose parents at some point served full-time in the military, no duration is specified or whether the parents had to be active duty, reserve or National Guard members. The prefix for the label comes from the military branch in which the parents primarily served, though like hyphenated names some younger generations will introduce themselves as a Navy-Air Force brat. Other sites suggest that it doesn’t refer to a spoiled child at all but actually is yet another of the acronyms that proliferate in military environments. Although after I read these possible theories, many seemed retrospective attempts to jettison the negative connotations.

I learned that like others sharing similar formative experiences, military brats are considered a subculture or a third culture, in some of the literature. There is a dearth of scholarly data about the phenomenology and social psychology of adults who spent some of their formative years under the auspices of military culture. As in any foray into cultural competence, avoiding stereotypes is crucial. However, research has shown that the experience of growing up in the military is one that bestows resilience and risk.³ It is also an important piece of a patient’s narrative that health care professionals in and out of the federal system should consider to provide patient-centered care.

A childhood in a military environment is often romanticized as shaping an adult who is worldly, cosmopolitan, resilient, and tolerant. Although these are adaptive traits that children of military personnel develop, there also is a far darker side emerging in the research.⁴ We are all too aware of the epidemic of suicide, opioid use, and posttraumatic stress disorder that has developed in the wake of our country’s latest and lasting conflicts. The reverberations of these mental health problems are felt by the children who lived through them or who lost loved ones to war or suicide. The DoD has begun recognizing this collateral damage and is developing innovative programs to help children and adolescents.

We need to do more though, not just in this arena when the wounds occur, but also later when those wounded come to nurse practitioners and psychologists, social workers, and physicians. Our growing number of community partners through Choice and other programs also need to be aware of the potential mental health impacts of being a military brat or family member.

In the introduction to one of the best books written on the subject, Military Brats: Legacies of Childhood Inside the Fortress, author Pat Conroy wrote, “I thought I was singular in all this, one of a kind.... I discovered that I speak in the multitongued, deep-throated voice of my tribe. It’s a language I was not even aware I spoke... a secret family I did not know I had.... Military brats, my lost tribe, spent their entire youth in service to this country, and no one even knew we were there.”⁵

Results from two new studies suggest that genetic testing early in the diagnostic pathway may allow for earlier and more precise diagnoses in early-life epilepsies and a range of other childhood-onset disorders, and potentially limit costs associated with a long diagnostic course.

Both papers, published online July 31 in JAMA Pediatrics, showed the diagnostic yield of genetic testing approaches, including whole-exome sequencing (WES), to be high.

The results also argue for the incorporation of genetic testing into the first diagnostic assessments; not limiting it to severe presentations only; and for broad testing methods to be employed in lieu of narrower ones.

Results from two new studies suggest that genetic testing early in the diagnostic pathway may allow for earlier and more precise diagnoses in early-life epilepsies and a range of other childhood-onset disorders, and potentially limit costs associated with a long diagnostic course.

Both papers, published online July 31 in JAMA Pediatrics, showed the diagnostic yield of genetic testing approaches, including whole-exome sequencing (WES), to be high.

The results also argue for the incorporation of genetic testing into the first diagnostic assessments; not limiting it to severe presentations only; and for broad testing methods to be employed in lieu of narrower ones.

Results from two new studies suggest that genetic testing early in the diagnostic pathway may allow for earlier and more precise diagnoses in early-life epilepsies and a range of other childhood-onset disorders, and potentially limit costs associated with a long diagnostic course.

Both papers, published online July 31 in JAMA Pediatrics, showed the diagnostic yield of genetic testing approaches, including whole-exome sequencing (WES), to be high.

The results also argue for the incorporation of genetic testing into the first diagnostic assessments; not limiting it to severe presentations only; and for broad testing methods to be employed in lieu of narrower ones.

Some patients with acute myeloid leukemia (AML) may have trouble with immunotherapy following chemotherapy. Researchers from the National Heart, Lung and Blood Institute may have found  a reason why.

Related: Novel Treatment Shows Promise for Acute Lymphoblastic Leukemia

 The researchers wanted to perform a “deep assessment” of the state of the adaptive immune system in AML patients in remission after chemotherapy. They used these patients’ response to seasonal influenza vaccination as a surrogate for the robustness of the immune system. The researchers say their approach was unique in that they established a comprehensive picture of the adaptive “immunome” by simultaneously examining the genetic, phenotypic, and functional consequences of chemotherapy.

Their assessment revealed a “dramatic impact” in the B-cell compartment, which appeared slower to recover than the T-cell compartment. Of 10 patients in the study, only 2 generated protective titers in response to vaccination. Most had abnormal frequencies of transitional and memory B-cells. The researchers say the inability of AML patients to produce protective antibody titers in response to influenza vaccination is likely due to multiple B-cell abnormalities.

Related: Six Open Clinical Trials That Are Expanding Our Understanding of Immunotherapies

The researchers “strikingly” found similar patterns of immune dysfunction across all the patients in the study. When they ranked patients based on time elapsed since chemotherapy, the degree of dysfunction was shown to be less in patients who had the most time elapsed form their chemotherapy treatment.

The researchers conclude the “consistent finding” of a reduction of memory B-cells in all the AML patients suggests that humoral immunity reconstitution is “a very long process.” They add that a better understanding of the changes in adaptive immune cell subsets after chemotherapy will be useful in designing immunotherapies that can work with existing immune capacity.

Source:
Goswami M, Prince G, Biancotto A, et al. J Transl Med. 2017;15:155.
doi:  10.1186/s12967-017-1252-2

Some patients with acute myeloid leukemia (AML) may have trouble with immunotherapy following chemotherapy. Researchers from the National Heart, Lung and Blood Institute may have found  a reason why.

Related: Novel Treatment Shows Promise for Acute Lymphoblastic Leukemia

 The researchers wanted to perform a “deep assessment” of the state of the adaptive immune system in AML patients in remission after chemotherapy. They used these patients’ response to seasonal influenza vaccination as a surrogate for the robustness of the immune system. The researchers say their approach was unique in that they established a comprehensive picture of the adaptive “immunome” by simultaneously examining the genetic, phenotypic, and functional consequences of chemotherapy.

Their assessment revealed a “dramatic impact” in the B-cell compartment, which appeared slower to recover than the T-cell compartment. Of 10 patients in the study, only 2 generated protective titers in response to vaccination. Most had abnormal frequencies of transitional and memory B-cells. The researchers say the inability of AML patients to produce protective antibody titers in response to influenza vaccination is likely due to multiple B-cell abnormalities.

Related: Six Open Clinical Trials That Are Expanding Our Understanding of Immunotherapies

The researchers “strikingly” found similar patterns of immune dysfunction across all the patients in the study. When they ranked patients based on time elapsed since chemotherapy, the degree of dysfunction was shown to be less in patients who had the most time elapsed form their chemotherapy treatment.

The researchers conclude the “consistent finding” of a reduction of memory B-cells in all the AML patients suggests that humoral immunity reconstitution is “a very long process.” They add that a better understanding of the changes in adaptive immune cell subsets after chemotherapy will be useful in designing immunotherapies that can work with existing immune capacity.

Source:
Goswami M, Prince G, Biancotto A, et al. J Transl Med. 2017;15:155.
doi:  10.1186/s12967-017-1252-2

Some patients with acute myeloid leukemia (AML) may have trouble with immunotherapy following chemotherapy. Researchers from the National Heart, Lung and Blood Institute may have found  a reason why.

Related: Novel Treatment Shows Promise for Acute Lymphoblastic Leukemia

 The researchers wanted to perform a “deep assessment” of the state of the adaptive immune system in AML patients in remission after chemotherapy. They used these patients’ response to seasonal influenza vaccination as a surrogate for the robustness of the immune system. The researchers say their approach was unique in that they established a comprehensive picture of the adaptive “immunome” by simultaneously examining the genetic, phenotypic, and functional consequences of chemotherapy.

Their assessment revealed a “dramatic impact” in the B-cell compartment, which appeared slower to recover than the T-cell compartment. Of 10 patients in the study, only 2 generated protective titers in response to vaccination. Most had abnormal frequencies of transitional and memory B-cells. The researchers say the inability of AML patients to produce protective antibody titers in response to influenza vaccination is likely due to multiple B-cell abnormalities.

Related: Six Open Clinical Trials That Are Expanding Our Understanding of Immunotherapies

The researchers “strikingly” found similar patterns of immune dysfunction across all the patients in the study. When they ranked patients based on time elapsed since chemotherapy, the degree of dysfunction was shown to be less in patients who had the most time elapsed form their chemotherapy treatment.

The researchers conclude the “consistent finding” of a reduction of memory B-cells in all the AML patients suggests that humoral immunity reconstitution is “a very long process.” They add that a better understanding of the changes in adaptive immune cell subsets after chemotherapy will be useful in designing immunotherapies that can work with existing immune capacity.

Source:
Goswami M, Prince G, Biancotto A, et al. J Transl Med. 2017;15:155.
doi:  10.1186/s12967-017-1252-2

Click here to access the August 2017 Digital Edition.

Table of Contents

• Collaboration of the NIH and PHS Commissioned Corps in the International Ebola Clinical Research Response
• Parkinsonism and Vitamin C Deficiency
• Right Paraduodenal Hernia
• Military Brats: Members of a Lost Tribe
• Practitioner Cognitive Reframing: Working More Effectively in Addictions
• The Role of Methicillin-Resistant Staphylococcus aureus Polymerase Chain Reaction Nasal Swabs in Clinical Decision Making
• Improving Veteran Engagement With Mental Health Care

Click here to access the August 2017 Digital Edition.

Table of Contents

• Collaboration of the NIH and PHS Commissioned Corps in the International Ebola Clinical Research Response
• Parkinsonism and Vitamin C Deficiency
• Right Paraduodenal Hernia
• Military Brats: Members of a Lost Tribe
• Practitioner Cognitive Reframing: Working More Effectively in Addictions
• The Role of Methicillin-Resistant Staphylococcus aureus Polymerase Chain Reaction Nasal Swabs in Clinical Decision Making
• Improving Veteran Engagement With Mental Health Care

Click here to access the August 2017 Digital Edition.

Table of Contents

• Collaboration of the NIH and PHS Commissioned Corps in the International Ebola Clinical Research Response
• Parkinsonism and Vitamin C Deficiency
• Right Paraduodenal Hernia
• Military Brats: Members of a Lost Tribe
• Practitioner Cognitive Reframing: Working More Effectively in Addictions
• The Role of Methicillin-Resistant Staphylococcus aureus Polymerase Chain Reaction Nasal Swabs in Clinical Decision Making
• Improving Veteran Engagement With Mental Health Care

Purpose: To present a lesson learned from a pilot project aiming to improve post-radiotherapy (RT) followup (FU) care for Veterans living in rural area within our VISN, thereby questioning if FU care as dictated by oncologic specialists would be beneficial in a rural Veteran’s cancer survivorship.

Methods: A team of radiation oncology (RO) specialists was assembled to include clinical providers and medical physicists. A 2-pronged approach was employed: 1 by inperson visit at selected rural community-based outpatient clinic (rCBOC), the other via telehealth link. Target population included rural Veterans who had received RT at either a VA or Non-VA Care Center (NVCC) facility. On-site visits were done by RO specialists at each rCBOC. Patient satisfaction was evaluated via feedback survey. Mileage and time saved were calculated for each Veteran who might otherwise travel to see a VA RO specialist.

Results: In a span of 14 months, 9 separate rCBOC visits were made for 3 sites and a total of 49 Veteran visits. Excellent patient satisfaction was obtained, and the average mileage and time saved per Veteran visit was 217.2 miles and 201 min (off-traffic peak), respectively. However, 4 of 5 NVCC treatment plans encountered contained physics quality assurance (QA) data not considered to have met professional standards. Dedicated telehealth equipment was acquired and connections validated. Challenges faced included: soliciting timely assistance of administrative leadership, identifying patients to be seen and accessing their records, and obtaining clinical privilege and EHR access at rCBOCs.

Implications: Access to post-treatment cancer care for rural Veterans can be improved with in-person visits by VA oncologic specialists at corresponding rCBOCs. Barriers due to distance and time can be reduced significantly, with excellent patient satisfaction outcome. The efficacy of telehealth link requires further clinical testing. Furthermore, the inadvertent finding of physics QA deficiencies at NVCC sites raised plausible concern for overall quality of RT care, reflecting the probable need for future oversight by VA specialists. By reaching out to rural Veterans proactively, VA oncologic specialists can enhance their post-treatment cancer care, thereby improving their cancer survivorship.

Purpose: To present a lesson learned from a pilot project aiming to improve post-radiotherapy (RT) followup (FU) care for Veterans living in rural area within our VISN, thereby questioning if FU care as dictated by oncologic specialists would be beneficial in a rural Veteran’s cancer survivorship.

Methods: A team of radiation oncology (RO) specialists was assembled to include clinical providers and medical physicists. A 2-pronged approach was employed: 1 by inperson visit at selected rural community-based outpatient clinic (rCBOC), the other via telehealth link. Target population included rural Veterans who had received RT at either a VA or Non-VA Care Center (NVCC) facility. On-site visits were done by RO specialists at each rCBOC. Patient satisfaction was evaluated via feedback survey. Mileage and time saved were calculated for each Veteran who might otherwise travel to see a VA RO specialist.

Results: In a span of 14 months, 9 separate rCBOC visits were made for 3 sites and a total of 49 Veteran visits. Excellent patient satisfaction was obtained, and the average mileage and time saved per Veteran visit was 217.2 miles and 201 min (off-traffic peak), respectively. However, 4 of 5 NVCC treatment plans encountered contained physics quality assurance (QA) data not considered to have met professional standards. Dedicated telehealth equipment was acquired and connections validated. Challenges faced included: soliciting timely assistance of administrative leadership, identifying patients to be seen and accessing their records, and obtaining clinical privilege and EHR access at rCBOCs.

Implications: Access to post-treatment cancer care for rural Veterans can be improved with in-person visits by VA oncologic specialists at corresponding rCBOCs. Barriers due to distance and time can be reduced significantly, with excellent patient satisfaction outcome. The efficacy of telehealth link requires further clinical testing. Furthermore, the inadvertent finding of physics QA deficiencies at NVCC sites raised plausible concern for overall quality of RT care, reflecting the probable need for future oversight by VA specialists. By reaching out to rural Veterans proactively, VA oncologic specialists can enhance their post-treatment cancer care, thereby improving their cancer survivorship.

Purpose: To present a lesson learned from a pilot project aiming to improve post-radiotherapy (RT) followup (FU) care for Veterans living in rural area within our VISN, thereby questioning if FU care as dictated by oncologic specialists would be beneficial in a rural Veteran’s cancer survivorship.

Methods: A team of radiation oncology (RO) specialists was assembled to include clinical providers and medical physicists. A 2-pronged approach was employed: 1 by inperson visit at selected rural community-based outpatient clinic (rCBOC), the other via telehealth link. Target population included rural Veterans who had received RT at either a VA or Non-VA Care Center (NVCC) facility. On-site visits were done by RO specialists at each rCBOC. Patient satisfaction was evaluated via feedback survey. Mileage and time saved were calculated for each Veteran who might otherwise travel to see a VA RO specialist.

Results: In a span of 14 months, 9 separate rCBOC visits were made for 3 sites and a total of 49 Veteran visits. Excellent patient satisfaction was obtained, and the average mileage and time saved per Veteran visit was 217.2 miles and 201 min (off-traffic peak), respectively. However, 4 of 5 NVCC treatment plans encountered contained physics quality assurance (QA) data not considered to have met professional standards. Dedicated telehealth equipment was acquired and connections validated. Challenges faced included: soliciting timely assistance of administrative leadership, identifying patients to be seen and accessing their records, and obtaining clinical privilege and EHR access at rCBOCs.

Implications: Access to post-treatment cancer care for rural Veterans can be improved with in-person visits by VA oncologic specialists at corresponding rCBOCs. Barriers due to distance and time can be reduced significantly, with excellent patient satisfaction outcome. The efficacy of telehealth link requires further clinical testing. Furthermore, the inadvertent finding of physics QA deficiencies at NVCC sites raised plausible concern for overall quality of RT care, reflecting the probable need for future oversight by VA specialists. By reaching out to rural Veterans proactively, VA oncologic specialists can enhance their post-treatment cancer care, thereby improving their cancer survivorship.