Doctor and patient

Photo courtesy of NIH

Patients who make 3 or more trips to the general practitioner (GP) before they are referred for cancer tests are more likely to be dissatisfied with subsequent care, according to research published in the European Journal of Cancer Care.

Researchers analyzed survey responses from nearly 60,000 cancer patients and found that about 23% had visited their GP 3 or more times before they were referred for cancer tests.

These patients were more likely than patients with 1 or 2 GP visits to report negative experiences with regard to many different aspects of their care.

“This research shows that first impressions go a long way in determining how cancer patients view their experience of cancer treatment,” said study author Georgios Lyratzopoulos, MD, of University College London in the UK.

“A negative experience of diagnosis can trigger loss of confidence in their care throughout the cancer journey. When they occur, diagnostic delays are largely due to cancer symptoms being extremely hard to distinguish from other diseases, combined with a lack of accurate and easy-to-use tests. New diagnostic tools to help doctors decide which patients need referring are vital to improve the care experience for even more cancer patients.”

Dr Lyratzopoulos and his colleagues initially analyzed survey data from 73,462 cancer patients, but 15,355 of those patients (21%) had not seen a GP prior to their cancer diagnosis.

Of the 58,107 patients who had at least 1 primary care consultation, 44,827 (77%) had seen their GP once or twice before referral for cancer tests, and 13,280 (23%) had seen the GP 3 or more times.

The researchers analyzed patients’ responses to 12 survey questions that assessed satisfaction with various aspects of their cancer care.

And results showed that patients who had seen their GP 3 or more times before referral were significantly more likely than patients with 1 to 2 GP visits to report negative experiences across 10 of the 12 aspects of care.

The 12 aspects of care and patient responses (for 3+ GP visits and 1-2 visits, respectively) were as follows:

1. Dissatisfied with overall care: 16% vs 9% (adjusted* odds ratio [aOR]=1.44, P<0.001)
2. Dissatisfied with the way they were informed of their cancer: 22% vs 14% (aOR=1.38, P<0.001)
3. Dissatisfied with their involvement in decision-making: 32% vs 25% (aOR=1.13, P<0.001)
4. Lack of confidence/trust in their doctors: 19% vs 12% (aOR=1.22, P<0.001)
5. Lack of confidence/trust in their nurses: 36% vs 27% (aOR=1.22, P<0.001)
6. Thought doctors/nurses deliberately withheld information: 16% vs 10% (aOR=1.27, P<0.001)
7. Dissatisfied with staff support: 41% vs 27% (aOR=1.68, P<0.001)
8. Dissatisfied with integration of various caregivers (GP, hospital doctors/nurses, specialist nurses, etc): 45% vs 32% (aOR=1.48, P<0.001)
9. Dissatisfied with the amount of time they had to wait at appointments with their hospital doctor: 31% vs 28% (aOR=1.10, P=0.007)
10. Said their GP did not receive enough information about their condition or hospital treatment: 8% vs 5% (aOR=1.36, P<0.001)
11. Said they did not receive clear written information about what they should or should not do after leaving the hospital: 20% vs 14% (aOR=1.06, P=0.100)
12. Said they did not receive the name of a Clinical Nurse Specialist who would be in charge of their care: 11% vs 9% (aOR=1.00, P=0.894).

“This is the first time we’ve had direct feedback from patients on such a large scale to show how the timeliness of their diagnosis colors their experience of the care they later receive,” said Sara Hiom, of Cancer Research UK, which supported this study.

“It’s another good reason to highlight the importance of diagnosing cancer as quickly as possible, not just to give patients the best chances of survival, but also to improve their experience of the care they receive throughout their cancer journey.”

*The odds ratio was adjusted for patient age, sex, ethnicity, cancer diagnosis, and response tendency (likelihood of giving a positive or negative response to questions).

Doctor and patient

Photo courtesy of NIH

Patients who make 3 or more trips to the general practitioner (GP) before they are referred for cancer tests are more likely to be dissatisfied with subsequent care, according to research published in the European Journal of Cancer Care.

Researchers analyzed survey responses from nearly 60,000 cancer patients and found that about 23% had visited their GP 3 or more times before they were referred for cancer tests.

These patients were more likely than patients with 1 or 2 GP visits to report negative experiences with regard to many different aspects of their care.

“This research shows that first impressions go a long way in determining how cancer patients view their experience of cancer treatment,” said study author Georgios Lyratzopoulos, MD, of University College London in the UK.

“A negative experience of diagnosis can trigger loss of confidence in their care throughout the cancer journey. When they occur, diagnostic delays are largely due to cancer symptoms being extremely hard to distinguish from other diseases, combined with a lack of accurate and easy-to-use tests. New diagnostic tools to help doctors decide which patients need referring are vital to improve the care experience for even more cancer patients.”

Dr Lyratzopoulos and his colleagues initially analyzed survey data from 73,462 cancer patients, but 15,355 of those patients (21%) had not seen a GP prior to their cancer diagnosis.

Of the 58,107 patients who had at least 1 primary care consultation, 44,827 (77%) had seen their GP once or twice before referral for cancer tests, and 13,280 (23%) had seen the GP 3 or more times.

The researchers analyzed patients’ responses to 12 survey questions that assessed satisfaction with various aspects of their cancer care.

And results showed that patients who had seen their GP 3 or more times before referral were significantly more likely than patients with 1 to 2 GP visits to report negative experiences across 10 of the 12 aspects of care.

The 12 aspects of care and patient responses (for 3+ GP visits and 1-2 visits, respectively) were as follows:

1. Dissatisfied with overall care: 16% vs 9% (adjusted* odds ratio [aOR]=1.44, P<0.001)
2. Dissatisfied with the way they were informed of their cancer: 22% vs 14% (aOR=1.38, P<0.001)
3. Dissatisfied with their involvement in decision-making: 32% vs 25% (aOR=1.13, P<0.001)
4. Lack of confidence/trust in their doctors: 19% vs 12% (aOR=1.22, P<0.001)
5. Lack of confidence/trust in their nurses: 36% vs 27% (aOR=1.22, P<0.001)
6. Thought doctors/nurses deliberately withheld information: 16% vs 10% (aOR=1.27, P<0.001)
7. Dissatisfied with staff support: 41% vs 27% (aOR=1.68, P<0.001)
8. Dissatisfied with integration of various caregivers (GP, hospital doctors/nurses, specialist nurses, etc): 45% vs 32% (aOR=1.48, P<0.001)
9. Dissatisfied with the amount of time they had to wait at appointments with their hospital doctor: 31% vs 28% (aOR=1.10, P=0.007)
10. Said their GP did not receive enough information about their condition or hospital treatment: 8% vs 5% (aOR=1.36, P<0.001)
11. Said they did not receive clear written information about what they should or should not do after leaving the hospital: 20% vs 14% (aOR=1.06, P=0.100)
12. Said they did not receive the name of a Clinical Nurse Specialist who would be in charge of their care: 11% vs 9% (aOR=1.00, P=0.894).

“This is the first time we’ve had direct feedback from patients on such a large scale to show how the timeliness of their diagnosis colors their experience of the care they later receive,” said Sara Hiom, of Cancer Research UK, which supported this study.

“It’s another good reason to highlight the importance of diagnosing cancer as quickly as possible, not just to give patients the best chances of survival, but also to improve their experience of the care they receive throughout their cancer journey.”

*The odds ratio was adjusted for patient age, sex, ethnicity, cancer diagnosis, and response tendency (likelihood of giving a positive or negative response to questions).

Doctor and patient

Photo courtesy of NIH

Patients who make 3 or more trips to the general practitioner (GP) before they are referred for cancer tests are more likely to be dissatisfied with subsequent care, according to research published in the European Journal of Cancer Care.

Researchers analyzed survey responses from nearly 60,000 cancer patients and found that about 23% had visited their GP 3 or more times before they were referred for cancer tests.

These patients were more likely than patients with 1 or 2 GP visits to report negative experiences with regard to many different aspects of their care.

“This research shows that first impressions go a long way in determining how cancer patients view their experience of cancer treatment,” said study author Georgios Lyratzopoulos, MD, of University College London in the UK.

“A negative experience of diagnosis can trigger loss of confidence in their care throughout the cancer journey. When they occur, diagnostic delays are largely due to cancer symptoms being extremely hard to distinguish from other diseases, combined with a lack of accurate and easy-to-use tests. New diagnostic tools to help doctors decide which patients need referring are vital to improve the care experience for even more cancer patients.”

Dr Lyratzopoulos and his colleagues initially analyzed survey data from 73,462 cancer patients, but 15,355 of those patients (21%) had not seen a GP prior to their cancer diagnosis.

Of the 58,107 patients who had at least 1 primary care consultation, 44,827 (77%) had seen their GP once or twice before referral for cancer tests, and 13,280 (23%) had seen the GP 3 or more times.

The researchers analyzed patients’ responses to 12 survey questions that assessed satisfaction with various aspects of their cancer care.

And results showed that patients who had seen their GP 3 or more times before referral were significantly more likely than patients with 1 to 2 GP visits to report negative experiences across 10 of the 12 aspects of care.

The 12 aspects of care and patient responses (for 3+ GP visits and 1-2 visits, respectively) were as follows:

1. Dissatisfied with overall care: 16% vs 9% (adjusted* odds ratio [aOR]=1.44, P<0.001)
2. Dissatisfied with the way they were informed of their cancer: 22% vs 14% (aOR=1.38, P<0.001)
3. Dissatisfied with their involvement in decision-making: 32% vs 25% (aOR=1.13, P<0.001)
4. Lack of confidence/trust in their doctors: 19% vs 12% (aOR=1.22, P<0.001)
5. Lack of confidence/trust in their nurses: 36% vs 27% (aOR=1.22, P<0.001)
6. Thought doctors/nurses deliberately withheld information: 16% vs 10% (aOR=1.27, P<0.001)
7. Dissatisfied with staff support: 41% vs 27% (aOR=1.68, P<0.001)
8. Dissatisfied with integration of various caregivers (GP, hospital doctors/nurses, specialist nurses, etc): 45% vs 32% (aOR=1.48, P<0.001)
9. Dissatisfied with the amount of time they had to wait at appointments with their hospital doctor: 31% vs 28% (aOR=1.10, P=0.007)
10. Said their GP did not receive enough information about their condition or hospital treatment: 8% vs 5% (aOR=1.36, P<0.001)
11. Said they did not receive clear written information about what they should or should not do after leaving the hospital: 20% vs 14% (aOR=1.06, P=0.100)
12. Said they did not receive the name of a Clinical Nurse Specialist who would be in charge of their care: 11% vs 9% (aOR=1.00, P=0.894).

“This is the first time we’ve had direct feedback from patients on such a large scale to show how the timeliness of their diagnosis colors their experience of the care they later receive,” said Sara Hiom, of Cancer Research UK, which supported this study.

“It’s another good reason to highlight the importance of diagnosing cancer as quickly as possible, not just to give patients the best chances of survival, but also to improve their experience of the care they receive throughout their cancer journey.”

*The odds ratio was adjusted for patient age, sex, ethnicity, cancer diagnosis, and response tendency (likelihood of giving a positive or negative response to questions).

Patients with acute pancreatitis who received pentoxifylline had fewer ICU admissions and shorter ICU and hospital stays than placebo-treated controls, according to a small, randomized double-blind trial reported in Gastroenterology.

“We showed that a single-institution drug trial for acute pancreatitis is feasible and that pentoxifylline is safe, cheap, and might have efficacy,” wrote Dr. Santhi Vege and his associates at the Mayo Clinic in Rochester, Minn. “This sets the stage for a larger trial of this drug in all patients with acute pancreatitis, to realize the goal of finding an effective drug that can be given within 24 hours of diagnosis in any setting.”

Tumor necrosis factor–alpha is a key culprit in severe acute pancreatitis, including pancreatic and peripancreatic necrosis, systemic inflammatory response syndrome, and persistent organ failure, the researchers noted. Pentoxifylline is a nonselective phosphodiesterase inhibitor that has been found safe and effective in other TNF-alpha–mediated diseases such as acute alcoholic hepatitis, but few studies in humans have evaluated the drug for acute pancreatitis, they said (Gastroenterology 2015 June 22 [doi:10.1053/j.gastro.2015.04.019]). For their study, the investigators randomized 28 patients with predicted severe acute pancreatitis to either placebo or 400 mg pentoxifylline given orally at enrollment and then three times a day for 72 hours. Both groups also received standard of care treatments such as antibiotics and fluid therapy, and had comparable baseline characteristics including age, sex, body mass index, Acute Physiology and Chronic Health Evaluation scores, systemic inflammatory response syndrome scores, and inflammatory marker levels, the researchers said.

Significantly fewer patients who received pentoxifylline needed to stay in the hospital for more than 4 days (14% vs. 57% for the placebo group; P = .046), and the maximum length of ICU stay was 0 days for the intervention group, compared with 13 days for the control group (P = .03), the investigators reported. Analyses of several other outcome measures also favored pentoxifylline over placebo, but did not reach statistical significance in the small study, including the need for ICU transfer (0% for pentoxifylline patients vs. 28% of the placebo group; P = .098) and the median length of hospitalization (for pentoxifylline: 3 days, range 1-5 days; for placebo: 5 days; range 1-30 days; P = .06).

The treatment and control groups did not significantly differ in terms of levels of inflammatory markers, including circulating TNF-alpha, said the investigators. Differences in levels of TNF-alpha, interleukin-6, IL-8, and C-reactive protein “may be significant if the sample size is larger,” they added.

The exact mechanism by which pentoxifylline affects acute pancreatitis is unclear, but the production of pancreatic TNF-alpha peaks about 24-36 hours into an episode of the disease, so patients might benefit from receiving pentoxifylline sooner than the 72-hour window dictated by the study protocol, said Dr. Vege and his associates. “Initiating drug therapy within a few hours is challenging, although a 24-hour cutoff time may be feasible in appropriate settings,” they wrote.

A scholarly opportunity award from the Mayo Clinic helped fund the work. The investigators reported having no relevant financial conflicts of interest.

Patients with acute pancreatitis who received pentoxifylline had fewer ICU admissions and shorter ICU and hospital stays than placebo-treated controls, according to a small, randomized double-blind trial reported in Gastroenterology.

“We showed that a single-institution drug trial for acute pancreatitis is feasible and that pentoxifylline is safe, cheap, and might have efficacy,” wrote Dr. Santhi Vege and his associates at the Mayo Clinic in Rochester, Minn. “This sets the stage for a larger trial of this drug in all patients with acute pancreatitis, to realize the goal of finding an effective drug that can be given within 24 hours of diagnosis in any setting.”

Tumor necrosis factor–alpha is a key culprit in severe acute pancreatitis, including pancreatic and peripancreatic necrosis, systemic inflammatory response syndrome, and persistent organ failure, the researchers noted. Pentoxifylline is a nonselective phosphodiesterase inhibitor that has been found safe and effective in other TNF-alpha–mediated diseases such as acute alcoholic hepatitis, but few studies in humans have evaluated the drug for acute pancreatitis, they said (Gastroenterology 2015 June 22 [doi:10.1053/j.gastro.2015.04.019]). For their study, the investigators randomized 28 patients with predicted severe acute pancreatitis to either placebo or 400 mg pentoxifylline given orally at enrollment and then three times a day for 72 hours. Both groups also received standard of care treatments such as antibiotics and fluid therapy, and had comparable baseline characteristics including age, sex, body mass index, Acute Physiology and Chronic Health Evaluation scores, systemic inflammatory response syndrome scores, and inflammatory marker levels, the researchers said.

Significantly fewer patients who received pentoxifylline needed to stay in the hospital for more than 4 days (14% vs. 57% for the placebo group; P = .046), and the maximum length of ICU stay was 0 days for the intervention group, compared with 13 days for the control group (P = .03), the investigators reported. Analyses of several other outcome measures also favored pentoxifylline over placebo, but did not reach statistical significance in the small study, including the need for ICU transfer (0% for pentoxifylline patients vs. 28% of the placebo group; P = .098) and the median length of hospitalization (for pentoxifylline: 3 days, range 1-5 days; for placebo: 5 days; range 1-30 days; P = .06).

The treatment and control groups did not significantly differ in terms of levels of inflammatory markers, including circulating TNF-alpha, said the investigators. Differences in levels of TNF-alpha, interleukin-6, IL-8, and C-reactive protein “may be significant if the sample size is larger,” they added.

The exact mechanism by which pentoxifylline affects acute pancreatitis is unclear, but the production of pancreatic TNF-alpha peaks about 24-36 hours into an episode of the disease, so patients might benefit from receiving pentoxifylline sooner than the 72-hour window dictated by the study protocol, said Dr. Vege and his associates. “Initiating drug therapy within a few hours is challenging, although a 24-hour cutoff time may be feasible in appropriate settings,” they wrote.

A scholarly opportunity award from the Mayo Clinic helped fund the work. The investigators reported having no relevant financial conflicts of interest.

Patients with acute pancreatitis who received pentoxifylline had fewer ICU admissions and shorter ICU and hospital stays than placebo-treated controls, according to a small, randomized double-blind trial reported in Gastroenterology.

“We showed that a single-institution drug trial for acute pancreatitis is feasible and that pentoxifylline is safe, cheap, and might have efficacy,” wrote Dr. Santhi Vege and his associates at the Mayo Clinic in Rochester, Minn. “This sets the stage for a larger trial of this drug in all patients with acute pancreatitis, to realize the goal of finding an effective drug that can be given within 24 hours of diagnosis in any setting.”

Tumor necrosis factor–alpha is a key culprit in severe acute pancreatitis, including pancreatic and peripancreatic necrosis, systemic inflammatory response syndrome, and persistent organ failure, the researchers noted. Pentoxifylline is a nonselective phosphodiesterase inhibitor that has been found safe and effective in other TNF-alpha–mediated diseases such as acute alcoholic hepatitis, but few studies in humans have evaluated the drug for acute pancreatitis, they said (Gastroenterology 2015 June 22 [doi:10.1053/j.gastro.2015.04.019]). For their study, the investigators randomized 28 patients with predicted severe acute pancreatitis to either placebo or 400 mg pentoxifylline given orally at enrollment and then three times a day for 72 hours. Both groups also received standard of care treatments such as antibiotics and fluid therapy, and had comparable baseline characteristics including age, sex, body mass index, Acute Physiology and Chronic Health Evaluation scores, systemic inflammatory response syndrome scores, and inflammatory marker levels, the researchers said.

Significantly fewer patients who received pentoxifylline needed to stay in the hospital for more than 4 days (14% vs. 57% for the placebo group; P = .046), and the maximum length of ICU stay was 0 days for the intervention group, compared with 13 days for the control group (P = .03), the investigators reported. Analyses of several other outcome measures also favored pentoxifylline over placebo, but did not reach statistical significance in the small study, including the need for ICU transfer (0% for pentoxifylline patients vs. 28% of the placebo group; P = .098) and the median length of hospitalization (for pentoxifylline: 3 days, range 1-5 days; for placebo: 5 days; range 1-30 days; P = .06).

The treatment and control groups did not significantly differ in terms of levels of inflammatory markers, including circulating TNF-alpha, said the investigators. Differences in levels of TNF-alpha, interleukin-6, IL-8, and C-reactive protein “may be significant if the sample size is larger,” they added.

The exact mechanism by which pentoxifylline affects acute pancreatitis is unclear, but the production of pancreatic TNF-alpha peaks about 24-36 hours into an episode of the disease, so patients might benefit from receiving pentoxifylline sooner than the 72-hour window dictated by the study protocol, said Dr. Vege and his associates. “Initiating drug therapy within a few hours is challenging, although a 24-hour cutoff time may be feasible in appropriate settings,” they wrote.

A scholarly opportunity award from the Mayo Clinic helped fund the work. The investigators reported having no relevant financial conflicts of interest.

A 53-year-old woman presented to the ED after experiencing a fall. Her medical history was significant for chronic obstructive pulmonary disease, hepatitis, and a remote history of intravenous drug use, for which she had been maintained on methadone for the past 20 years. She reported that she had suffered several “fainting episodes” over the past month, and the morning prior to arrival, had sustained what she thought was a mechanical fall outside of the methadone program she attended. She complained of tenderness on her head but denied any other injuries.

The methadone program had referred the patient to the ED for evaluation, noting to the ED staff that her daily methadone dose of 185 mg had not been dispensed prior to transfer. During evaluation, the patient requested that the emergency physician (EP) provide the methadone dose since the clinic would close prior to her discharge from the ED. 

How can requests for methadone be managed in the ED?

Methadone is a long-acting oral opioid that is used for both opioid replacement therapy and pain management. When used to reduce craving in opioid-dependent patients, methadone is administered daily through federally sanctioned methadone maintenance treatment (MMT) programs. Patients who consistently adhere to the required guidelines are given “take home” doses. When used for pain management, methadone is typically administered several times daily and may be prescribed by any provider with an appropriate DEA registration.

When given for MMT, methadone saturates the µ-opioid receptors and hinders their binding and agonism by other opioids such as heroin or oxycodone. Patients in MMT programs are started on a low initial dose and slowly titrated upward as tolerance to the adverse effects (eg, sedation) develop.

How are symptomatic patients with methadone withdrawal treated?

Most methadone programs have limited hours and require that patients who miss a dose wait until the following day to return to the program. This is typically without medical consequence because the high dose dispensed by these programs maintains a therapeutic blood concentration for far longer than the expected delay. Although the half-life of methadone exhibits wide interindividual variability, it generally ranges from 12 hours to more than 40 hours.¹ Regardless, patients may feel anxious about potential opioid withdrawal, and this often leads them to access the ED for a missed dose.

The neuropsychiatric symptoms attending withdrawal may precede the objective signs of opioid withdrawal. Patients with objective signs of opioid withdrawal (eg, piloerection, vomiting, diarrhea, dilated pupils) may be sufficiently treated with supportive care alone, using antiemetics, hydration, and sometimes clonidine.

Administration of substitute opioids is problematic due to the patient’s underlying tolerance necessitating careful dose titration. Therefore, direct replacement of methadone in the ED remains controversial, and some EDs have strict policies prohibiting the administration of methadone to patients who have missed an MMT dose. Such policies, which are intended to discourage patients from using the ED as a convenience, may be appropriate given the generally benign—though uncomfortable—course of opioid withdrawal due to abstinence.

Other EDs provide replacement methadone for asymptomatic, treat-and-release patients confirmed to be enrolled in an MMT program when the time to the next dose is likely to be 24 hours or greater from the missed dose. Typically, a dose of no more than 10 mg orally or 10 mg intramuscularly (IM) is recommended, and patients should be advised that they will be receiving only a low dose to sufficient to prevent withdrawal—one that may not have the equivalent effects of the outpatient dose.

Whenever possible, a patient’s MMT program should be contacted and informed of the ED visit. For patients who display objective signs of withdrawal and who cannot be confirmed or who do not participate in an MMT program, 10 mg of methadone IM will prevent uncertainty of drug absorption in the setting of nausea or vomiting. All patients receiving oral methadone should be observed for 1 hour, and those receiving IM methadone should be observed for at least 90 minutes to assess for unexpected sedation.²

Patients encountering circumstances that prevent opioid access (eg, incarceration) and who are not in withdrawal but have gone without opioids for more than 5 days may have a loss of tolerance to their usual doses—whether the medication was obtained through an MMT program or illicitly. Harm-reduction strategies aimed at educating patients on the potential vulnerability to their familiar dosing regimens are warranted to avert inadvertent overdoses in chronic opioid users who are likely to resume illicit opoiod use.

Does this patient need syncope evaluation?

Further complicating the decision regarding ED dispensing of methadone are the effects of the drug on myocardial repolarization. Methadone affects conduction across the hERG potassium rectifier current and can prolong the QTc interval on the surface electrocardiogram (ECG), predisposing a patient to torsade de pointes (TdP). Although there is controversy regarding the role of ECG screening during the enrollment of patients in methadone maintenance clinics, doses above 60 mg, underlying myocardial disease, female sex, and electrolyte disturbances may increase the risk of QT prolongation and TdP.³

Whether there is value in obtaining a screening ECG in a patient receiving an initial dose of methadone in the ED is unclear, and this practice is controversial even among methadone clinics. However, some of the excess death in patients taking methadone may be explained by the dysrhythmogenic potential of methadone.⁴ An ECG therefore may elucidate a correctable cause in methadone patients presenting with syncope.  

Administering methadone to patients with documented QT prolongation must weigh the risk of methadone’s conduction effects against the substantial risks of illicit opioid self-administration. For some patients at-risk for TdP, it may be preferable to use buprenorphine if possible, since it does not carry the same cardiac effects as methadone.^1,5 Such therapy requires referral to a physician licensed to prescribe this medication.

How should admitted patients be managed?

While administration of methadone for withdrawal or maintenance therapy in the ED is acceptable, outpatient prescribing of methadone for these reasons is not legal, and only federally regulated clinics may engage in this practice. Hospitalized patients who are enrolled in an MMT program should have their daily methadone dose confirmed and continued—as long as the patient has not lost tolerance. Patients not participating in an MMT program can receive up to 3 days of methadone in the hospital, even if the practitioner is not registered to provide methadone.⁶ For these patients, it is recommended that the physician order a low dose of methadone and also consult with an addiction specialist to determine whether the patient should continue on MMT maintenance or undergo detoxification.

It is important to note that methadone may be prescribed for pain, but its use in the ED for this purpose is strongly discouraged, especially in patients who have never received methadone previously. For admitted patients requiring such potent opioid analgesia, consultation with a pain service or, when indicated, a palliative care/hospice specialist is warranted as the dosing intervals are different in each setting, and the risk of respiratory depression is high.

Case Conclusion

As requested by the MMT clinic, the patient was administered methadone 185 mg orally in the ED, though a dose of 10 mg would have been sufficient to prevent withdrawal. Unfortunately, the EP did not appreciate the relationship of the markedly prolonged QTc and the methadone, which should have prompted a dose reduction.

Evaluation of the patient’s electrolyte levels, which included magnesium and potassium, were normal. An ECG was repeated 24 hours later and revealed a persistent, but improved, QT interval at 505 ms. The remainder of the syncope workup was negative. Because the patient had no additional symptoms or events during her stay, she was discharged. At discharge, the EP followed up with the MMT clinic to discuss lowering the patient’s daily methadone dose, as well as close cardiology follow-up.

Dr Rao is the chief of the division of medical toxicology at New York Presbyterian Hospital/Weill Cornell Medical Center, New York. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board.

A 53-year-old woman presented to the ED after experiencing a fall. Her medical history was significant for chronic obstructive pulmonary disease, hepatitis, and a remote history of intravenous drug use, for which she had been maintained on methadone for the past 20 years. She reported that she had suffered several “fainting episodes” over the past month, and the morning prior to arrival, had sustained what she thought was a mechanical fall outside of the methadone program she attended. She complained of tenderness on her head but denied any other injuries.

The methadone program had referred the patient to the ED for evaluation, noting to the ED staff that her daily methadone dose of 185 mg had not been dispensed prior to transfer. During evaluation, the patient requested that the emergency physician (EP) provide the methadone dose since the clinic would close prior to her discharge from the ED. 

How can requests for methadone be managed in the ED?

Methadone is a long-acting oral opioid that is used for both opioid replacement therapy and pain management. When used to reduce craving in opioid-dependent patients, methadone is administered daily through federally sanctioned methadone maintenance treatment (MMT) programs. Patients who consistently adhere to the required guidelines are given “take home” doses. When used for pain management, methadone is typically administered several times daily and may be prescribed by any provider with an appropriate DEA registration.

When given for MMT, methadone saturates the µ-opioid receptors and hinders their binding and agonism by other opioids such as heroin or oxycodone. Patients in MMT programs are started on a low initial dose and slowly titrated upward as tolerance to the adverse effects (eg, sedation) develop.

How are symptomatic patients with methadone withdrawal treated?

Most methadone programs have limited hours and require that patients who miss a dose wait until the following day to return to the program. This is typically without medical consequence because the high dose dispensed by these programs maintains a therapeutic blood concentration for far longer than the expected delay. Although the half-life of methadone exhibits wide interindividual variability, it generally ranges from 12 hours to more than 40 hours.¹ Regardless, patients may feel anxious about potential opioid withdrawal, and this often leads them to access the ED for a missed dose.

The neuropsychiatric symptoms attending withdrawal may precede the objective signs of opioid withdrawal. Patients with objective signs of opioid withdrawal (eg, piloerection, vomiting, diarrhea, dilated pupils) may be sufficiently treated with supportive care alone, using antiemetics, hydration, and sometimes clonidine.

Administration of substitute opioids is problematic due to the patient’s underlying tolerance necessitating careful dose titration. Therefore, direct replacement of methadone in the ED remains controversial, and some EDs have strict policies prohibiting the administration of methadone to patients who have missed an MMT dose. Such policies, which are intended to discourage patients from using the ED as a convenience, may be appropriate given the generally benign—though uncomfortable—course of opioid withdrawal due to abstinence.

Other EDs provide replacement methadone for asymptomatic, treat-and-release patients confirmed to be enrolled in an MMT program when the time to the next dose is likely to be 24 hours or greater from the missed dose. Typically, a dose of no more than 10 mg orally or 10 mg intramuscularly (IM) is recommended, and patients should be advised that they will be receiving only a low dose to sufficient to prevent withdrawal—one that may not have the equivalent effects of the outpatient dose.

Whenever possible, a patient’s MMT program should be contacted and informed of the ED visit. For patients who display objective signs of withdrawal and who cannot be confirmed or who do not participate in an MMT program, 10 mg of methadone IM will prevent uncertainty of drug absorption in the setting of nausea or vomiting. All patients receiving oral methadone should be observed for 1 hour, and those receiving IM methadone should be observed for at least 90 minutes to assess for unexpected sedation.²

Patients encountering circumstances that prevent opioid access (eg, incarceration) and who are not in withdrawal but have gone without opioids for more than 5 days may have a loss of tolerance to their usual doses—whether the medication was obtained through an MMT program or illicitly. Harm-reduction strategies aimed at educating patients on the potential vulnerability to their familiar dosing regimens are warranted to avert inadvertent overdoses in chronic opioid users who are likely to resume illicit opoiod use.

Does this patient need syncope evaluation?

Further complicating the decision regarding ED dispensing of methadone are the effects of the drug on myocardial repolarization. Methadone affects conduction across the hERG potassium rectifier current and can prolong the QTc interval on the surface electrocardiogram (ECG), predisposing a patient to torsade de pointes (TdP). Although there is controversy regarding the role of ECG screening during the enrollment of patients in methadone maintenance clinics, doses above 60 mg, underlying myocardial disease, female sex, and electrolyte disturbances may increase the risk of QT prolongation and TdP.³

Whether there is value in obtaining a screening ECG in a patient receiving an initial dose of methadone in the ED is unclear, and this practice is controversial even among methadone clinics. However, some of the excess death in patients taking methadone may be explained by the dysrhythmogenic potential of methadone.⁴ An ECG therefore may elucidate a correctable cause in methadone patients presenting with syncope.  

Administering methadone to patients with documented QT prolongation must weigh the risk of methadone’s conduction effects against the substantial risks of illicit opioid self-administration. For some patients at-risk for TdP, it may be preferable to use buprenorphine if possible, since it does not carry the same cardiac effects as methadone.^1,5 Such therapy requires referral to a physician licensed to prescribe this medication.

How should admitted patients be managed?

While administration of methadone for withdrawal or maintenance therapy in the ED is acceptable, outpatient prescribing of methadone for these reasons is not legal, and only federally regulated clinics may engage in this practice. Hospitalized patients who are enrolled in an MMT program should have their daily methadone dose confirmed and continued—as long as the patient has not lost tolerance. Patients not participating in an MMT program can receive up to 3 days of methadone in the hospital, even if the practitioner is not registered to provide methadone.⁶ For these patients, it is recommended that the physician order a low dose of methadone and also consult with an addiction specialist to determine whether the patient should continue on MMT maintenance or undergo detoxification.

It is important to note that methadone may be prescribed for pain, but its use in the ED for this purpose is strongly discouraged, especially in patients who have never received methadone previously. For admitted patients requiring such potent opioid analgesia, consultation with a pain service or, when indicated, a palliative care/hospice specialist is warranted as the dosing intervals are different in each setting, and the risk of respiratory depression is high.

Case Conclusion

As requested by the MMT clinic, the patient was administered methadone 185 mg orally in the ED, though a dose of 10 mg would have been sufficient to prevent withdrawal. Unfortunately, the EP did not appreciate the relationship of the markedly prolonged QTc and the methadone, which should have prompted a dose reduction.

Evaluation of the patient’s electrolyte levels, which included magnesium and potassium, were normal. An ECG was repeated 24 hours later and revealed a persistent, but improved, QT interval at 505 ms. The remainder of the syncope workup was negative. Because the patient had no additional symptoms or events during her stay, she was discharged. At discharge, the EP followed up with the MMT clinic to discuss lowering the patient’s daily methadone dose, as well as close cardiology follow-up.

Dr Rao is the chief of the division of medical toxicology at New York Presbyterian Hospital/Weill Cornell Medical Center, New York. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board.

A 53-year-old woman presented to the ED after experiencing a fall. Her medical history was significant for chronic obstructive pulmonary disease, hepatitis, and a remote history of intravenous drug use, for which she had been maintained on methadone for the past 20 years. She reported that she had suffered several “fainting episodes” over the past month, and the morning prior to arrival, had sustained what she thought was a mechanical fall outside of the methadone program she attended. She complained of tenderness on her head but denied any other injuries.

The methadone program had referred the patient to the ED for evaluation, noting to the ED staff that her daily methadone dose of 185 mg had not been dispensed prior to transfer. During evaluation, the patient requested that the emergency physician (EP) provide the methadone dose since the clinic would close prior to her discharge from the ED. 

How can requests for methadone be managed in the ED?

Methadone is a long-acting oral opioid that is used for both opioid replacement therapy and pain management. When used to reduce craving in opioid-dependent patients, methadone is administered daily through federally sanctioned methadone maintenance treatment (MMT) programs. Patients who consistently adhere to the required guidelines are given “take home” doses. When used for pain management, methadone is typically administered several times daily and may be prescribed by any provider with an appropriate DEA registration.

When given for MMT, methadone saturates the µ-opioid receptors and hinders their binding and agonism by other opioids such as heroin or oxycodone. Patients in MMT programs are started on a low initial dose and slowly titrated upward as tolerance to the adverse effects (eg, sedation) develop.

How are symptomatic patients with methadone withdrawal treated?

Most methadone programs have limited hours and require that patients who miss a dose wait until the following day to return to the program. This is typically without medical consequence because the high dose dispensed by these programs maintains a therapeutic blood concentration for far longer than the expected delay. Although the half-life of methadone exhibits wide interindividual variability, it generally ranges from 12 hours to more than 40 hours.¹ Regardless, patients may feel anxious about potential opioid withdrawal, and this often leads them to access the ED for a missed dose.

The neuropsychiatric symptoms attending withdrawal may precede the objective signs of opioid withdrawal. Patients with objective signs of opioid withdrawal (eg, piloerection, vomiting, diarrhea, dilated pupils) may be sufficiently treated with supportive care alone, using antiemetics, hydration, and sometimes clonidine.

Administration of substitute opioids is problematic due to the patient’s underlying tolerance necessitating careful dose titration. Therefore, direct replacement of methadone in the ED remains controversial, and some EDs have strict policies prohibiting the administration of methadone to patients who have missed an MMT dose. Such policies, which are intended to discourage patients from using the ED as a convenience, may be appropriate given the generally benign—though uncomfortable—course of opioid withdrawal due to abstinence.

Other EDs provide replacement methadone for asymptomatic, treat-and-release patients confirmed to be enrolled in an MMT program when the time to the next dose is likely to be 24 hours or greater from the missed dose. Typically, a dose of no more than 10 mg orally or 10 mg intramuscularly (IM) is recommended, and patients should be advised that they will be receiving only a low dose to sufficient to prevent withdrawal—one that may not have the equivalent effects of the outpatient dose.

Whenever possible, a patient’s MMT program should be contacted and informed of the ED visit. For patients who display objective signs of withdrawal and who cannot be confirmed or who do not participate in an MMT program, 10 mg of methadone IM will prevent uncertainty of drug absorption in the setting of nausea or vomiting. All patients receiving oral methadone should be observed for 1 hour, and those receiving IM methadone should be observed for at least 90 minutes to assess for unexpected sedation.²

Patients encountering circumstances that prevent opioid access (eg, incarceration) and who are not in withdrawal but have gone without opioids for more than 5 days may have a loss of tolerance to their usual doses—whether the medication was obtained through an MMT program or illicitly. Harm-reduction strategies aimed at educating patients on the potential vulnerability to their familiar dosing regimens are warranted to avert inadvertent overdoses in chronic opioid users who are likely to resume illicit opoiod use.

Does this patient need syncope evaluation?

Further complicating the decision regarding ED dispensing of methadone are the effects of the drug on myocardial repolarization. Methadone affects conduction across the hERG potassium rectifier current and can prolong the QTc interval on the surface electrocardiogram (ECG), predisposing a patient to torsade de pointes (TdP). Although there is controversy regarding the role of ECG screening during the enrollment of patients in methadone maintenance clinics, doses above 60 mg, underlying myocardial disease, female sex, and electrolyte disturbances may increase the risk of QT prolongation and TdP.³

Whether there is value in obtaining a screening ECG in a patient receiving an initial dose of methadone in the ED is unclear, and this practice is controversial even among methadone clinics. However, some of the excess death in patients taking methadone may be explained by the dysrhythmogenic potential of methadone.⁴ An ECG therefore may elucidate a correctable cause in methadone patients presenting with syncope.  

Administering methadone to patients with documented QT prolongation must weigh the risk of methadone’s conduction effects against the substantial risks of illicit opioid self-administration. For some patients at-risk for TdP, it may be preferable to use buprenorphine if possible, since it does not carry the same cardiac effects as methadone.^1,5 Such therapy requires referral to a physician licensed to prescribe this medication.

How should admitted patients be managed?

While administration of methadone for withdrawal or maintenance therapy in the ED is acceptable, outpatient prescribing of methadone for these reasons is not legal, and only federally regulated clinics may engage in this practice. Hospitalized patients who are enrolled in an MMT program should have their daily methadone dose confirmed and continued—as long as the patient has not lost tolerance. Patients not participating in an MMT program can receive up to 3 days of methadone in the hospital, even if the practitioner is not registered to provide methadone.⁶ For these patients, it is recommended that the physician order a low dose of methadone and also consult with an addiction specialist to determine whether the patient should continue on MMT maintenance or undergo detoxification.

It is important to note that methadone may be prescribed for pain, but its use in the ED for this purpose is strongly discouraged, especially in patients who have never received methadone previously. For admitted patients requiring such potent opioid analgesia, consultation with a pain service or, when indicated, a palliative care/hospice specialist is warranted as the dosing intervals are different in each setting, and the risk of respiratory depression is high.

Case Conclusion

As requested by the MMT clinic, the patient was administered methadone 185 mg orally in the ED, though a dose of 10 mg would have been sufficient to prevent withdrawal. Unfortunately, the EP did not appreciate the relationship of the markedly prolonged QTc and the methadone, which should have prompted a dose reduction.

Evaluation of the patient’s electrolyte levels, which included magnesium and potassium, were normal. An ECG was repeated 24 hours later and revealed a persistent, but improved, QT interval at 505 ms. The remainder of the syncope workup was negative. Because the patient had no additional symptoms or events during her stay, she was discharged. At discharge, the EP followed up with the MMT clinic to discuss lowering the patient’s daily methadone dose, as well as close cardiology follow-up.

Dr Rao is the chief of the division of medical toxicology at New York Presbyterian Hospital/Weill Cornell Medical Center, New York. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board.

Children are not the only people affected by attention-deficit/hyperactivity disorder (ADHD). Characterized by high levels of inattention, overactivity, and impulsivity, ADHD affects 5% of school-aged children, but also 4% of adults.^1–3 Adults with untreated ADHD are likely to develop serious psychosocial problems that manifest as unemployment, arrests, divorce, underachievement, and psychiatric comorbidities.^4,5

However, many clinicians are reluctant to manage adults with ADHD, partly because of concerns about misuse of the stimulant drugs they must prescribe to treat it.

Here, we outline an approach whereby clinicians can diagnose and treat adult ADHD while taking “universal precautions” to discourage misuse of the medications involved.

RECOGNIZING ADHD IN ADULTS

ADHD is characterized by developmentally inappropriate levels of inattention, impulsiveness, and hyperactivity that arise in childhood and result in impairments that often persist.

The presentation of ADHD in adults may be influenced by the longevity of their ADHD, associated sequelae (eg, low self-esteem and interpersonal, educational, and occupational difficulties), and comorbid disorders.⁶ There are neither reliable biomarkers nor neuropsychological tests for diagnosis, and persons with ADHD typically have a complex presentation with at least one comorbidity.^6,7

In patients diagnosed in childhood, difficulties with organization as well as initiating, maintaining, and completing tasks become more prominent in adulthood and hyperactivity tends to subside. Adult impulsivity may present as edginess, shopping sprees, quitting jobs, and risky behaviors.⁶

Overall, the clinical manifestations of ADHD in adolescents and adults include inattention, difficulties with task completion, disorganization, and executive dysfunction—all skills critical to managing the various roles of adult life.

OBSTACLES TO EFFECTIVE TREATMENT

In the past, ADHD treatment was routinely discontinued during adolescence, as it was unclear whether adults still had significant symptoms or benefited from treatment.^8,9 Now, available ADHD guidelines suggest that children and adults who respond to pharmacotherapy should continue it for as long as it remains effective. In this context, there is increasing recognition of adult ADHD as a valid and treatable disorder.¹⁰

Adults with ADHD tend to lack critical skills to manage the various roles of adult life

One of the challenges clinicians face is the reliability of adult recall of childhood ADHD. A controlled, prospective 16-year follow-up study found that of all adults retrospectively given a diagnosis of childhood ADHD, only 27% actually had the disorder.¹¹ This study suggests that retrospective diagnoses of childhood ADHD made solely on the basis of self-reports are unlikely to be valid.

Another obstacle is that traditional medical education has seldom included training in adult ADHD.^8,12 In a UK study, clinicians felt that they lacked training and knowledge to assess and manage adult ADHD patients.⁹

Even if adult ADHD is recognized, diagnosis is just the first step of care.¹³ These patients require ongoing management and follow-up assessments.

Although practice patterns vary, efforts to encourage doctors to provide adult ADHD care may be hindered by the fact that the gold standard of treatment is stimulant medication.^4,10 Medications approved by the US Food and Drug Administration for adult ADHD include the stimulants lisdexamfetamine, osmotic-release methylphenidate, mixed amphetamine salts extended release, dexmethylphenidate extended release, and the nonstimulant atomoxetine.⁶ While stimulants are generally more efficacious for ADHD symptoms than nonstimulants, they are associated with misuse and diversion.¹⁴

UNIVERSAL PRECAUTIONS: A SIMPLIFIED APPROACH

The universal-precautions approach to prescribing stimulants aims to allay physician concerns and promote appropriate medication use to allow for proper management of this disorder.¹⁵ These precautions, to be applied to all adult ADHD patients for whom stimulants are being considered, include careful diagnosis and consideration of comorbidities, baseline risk stratification, informed consent processes, treatment agreements, periodic reassessments of treatment response, and meticulous documentation.

DIAGNOSIS

A frequently used screening assessment for adult ADHD is the ADHD Rating Scale (ADHD RS), which consists of two subscales for assessing hyperactivity/impulsivity and inattentiveness.¹⁶ ADHD can be classified into one of three subtypes based on symptoms: inattentive, hyperactive, or combined type. Symptoms must persist for at least 6 months for a diagnosis to be made. Other ADHD scales include the Conners Adult ADHD Rating Scales and the Brown Attention-Deficit Disorder Scales.⁴

High scores on screening scales must be interpreted within the clinical context. Clinicians need to ask about ADHD symptoms, establish their presence in various settings, and determine if these symptoms interfere with functioning. A diagnosis of adult ADHD also requires evidence of symptoms beginning in childhood.¹⁷ According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, inattentive or hyperactive-impulsive symptoms must be present before age 12 in two or more settings and interfere with function and development.

Although self-reporting screening tools are helpful, these tests are not reliable for diagnostic purposes, and collateral information is also required.

Neuropsychological testing may detect impairments in persons with ADHD. The most consistently employed neuropsychological tests to evaluate ADHD include the Conners Continuous Performance Test, Stroop Color and Word Test, Trail-making Test, verbal fluency tests, Controlled Oral Word Association Test, and the Weschler Adult Intelligence Scale.⁶

COMORBIDITY

Epidemiologic studies suggest that adults with ADHD develop many psychiatric problems including anxiety, depression, and substance use disorders.^7,16 Table 1 illustrates common comorbidities and their associated prevalence in the ADHD patient.⁷

Comorbid psychiatric disorders may affect the presentation of adult ADHD. For instance, adults with comorbid depression and ADHD are more likely to present with heightened irritability and difficulties concentrating on tasks than those with either condition alone.¹⁸ Similarly, antisocial personality disorder is more common in adults with ADHD.¹⁹ Such patients exhibit stable antisocial behavior (lying, stealing, and aggression) as well as medication misuse.^5,14,19

While these comorbid disorders may obscure the ADHD diagnosis, their recognition is essential to effectively manage adult ADHD. In sum, a careful evaluation of the adult, including elucidating both ADHD and comorbid symptoms, functionality in several domains, and the degree of impairment, should precede initiating pharmacotherapy for adult ADHD.

BASELINE RISK STRATIFICATION: RISK FACTORS FOR STIMULANT MISUSE

After diagnosing ADHD, the prescriber must assess the risk for misuse of stimulant medications.²⁰

One study revealed that nonmedical use of stimulant medications occurred in only 2% of the 4,300 people surveyed.²¹ Among the misusers, 66% had obtained medication from family or friends. Another 34% had stolen medication, and 20% had obtained prescriptions from a physician by falsely reporting symptoms. The study also assessed motivation for misuse. In this sample, 40% of misuse was to enhance performance, 34% was for recreation, and 23% was to stay awake.²¹

Other studies show that misuse of stimulant medications is common among youth in the United States, reporting that 18% of college students use some formulation of prescription stimulants.²²

Still more research suggests that childhood conduct disorder or illicit drug use results in a higher risk of stimulant medication misuse.²⁰ Additional risk factors for misuse include male sex, white ethnicity, upper-class background, Jewish or no religious affiliation, affiliation with a sorority or fraternity, off-campus housing, and a low grade-point average.²³

Table 2 illustrates clinical interventions providers can use, once they have risk-stratified their patients, to monitor for stimulant misuse.

HOW SHOULD THESE RISK FACTORS AFFECT TREATMENT?

Although no formal scoring system exists to help clinicians risk-stratify these patients, the presence of multiple risk factors suggests the need for vigilance.¹⁴ Physicians should prescribe agents with less potential for abuse and monitor these patients more intensely.

Short-acting stimulant medications are the most likely to be abused, as phasic dopamine increase is more reinforcing than therapeutic dopamine release.²⁴ Longer-acting stimulant medications are less likely to be abused, and they provide better symptom relief, as tonic dopamine release maintains a steady state and increases the therapeutic efficacy of these medications.²⁵ For example, methylphenidate extended-release tablets have an osmotic oral controlled-release system and are less likely to be crushed for recreational inhalation.^6,14

Lisdexamfetamine is a prodrug therapeutically inert until converted to d-amphetamine when lysine is cleaved from the molecule. This medication may be a good option for patients at high risk of misuse because it is tamper-resistant. However, it still may be subject to misuse for performance enhancement.^26,27

The nonstimulant atomoxetine is also approved for ADHD, has no abuse potential, and may be particularly useful when anxiety, mood, and substance use disorders co-occur with ADHD.⁶ Rarely, atomoxetine can damage the liver, and liver function tests should be monitored if right upper quadrant pain develops.^4,10

Other nonapproved agents such as bupropion and desipramine also have been used empirically and off-label for ADHD.^4,10

Overall, treatment should be selected according to the risk of misuse of stimulant medication and the patient’s comorbidities.

INFORMED CONSENT

Informed consent may help patients appreciate the risks and benefits of the treatment options and develop realistic expectations about treatment.²⁶ Patients are instructed to take their stimulant medications as prescribed and are informed of the risks of combining stimulants with other substances, particularly those that may interact with stimulants (eg, cocaine) and raise the risk of seizures and cardiovascular complications.

Stimulant medications lead to elevations in blood pressure and heart rate, although  large-scale studies have shown no increase in the rate of serious cardiovascular events when these drugs are used appropriately.⁶ Less serious side effects associated with stimulant medications include insomnia, weight loss, decreased appetite, dry mouth, headache, and rarely, depression and anxiety.⁶

Patients need to be warned about diversion and abuse liability of stimulant medications, as well as alternative treatments.

The nonstimulant atomoxetine has no reinforcing properties but also raises the blood pressure and heart rate.⁶ As with stimulants, these elevations are generally minimal, time-limited, and of minor clinical significance.^4,10 Frequent reasons to prescribe atomoxetine include poor tolerability of stimulants and a history of substance abuse. In addition, women with ADHD and high levels of emotional dysregulation or social anxiety appear to be particularly responsive to atomoxetine.⁶

Another consideration is cognitive behavioral therapy, which can augment the effects of pharmacotherapy.⁴ Cognitive behavioral therapy focuses on time management, prioritization, organization, problem-solving, motivation, and emotional regulation.⁴

Finally, patients also need to understand the possible consequences of nontreatment.⁵ Adults with untreated ADHD have high rates of academic and occupational difficulties, anti-social behaviors, and other forms of psychosocial adversity.^4,5

Overall, this process should involve discussing risks and benefits of treatment options with the patient and promoting joint decision-making.

TREATMENT AGREEMENTS

Stimulant medications are classified by the US Drug Enforcement Administration as schedule II substances due to their abuse potential.²⁰

It is important to inform patients of the addictive nature of the medication and to instruct them on how to store stimulants safely.²⁷ Patients need to know that giving away or selling these medications is illegal.²⁷

After diagnosing adult ADHD, assess the risk for misuse of stimulant medications

Treatment agreements establish rules for prescribing and are signed by the patient before initiating therapy.^28,29 Patients are expected to attend all of their appointments, receive their prescriptions from one doctor, and obtain their medication from one pharmacy. These agreements may also require patients to submit to monitoring with random urine drug screens.²⁹ Overall, they underscore the need for patients to follow a treatment plan in order to continue therapy with controlled substances.²⁹

Manning²⁷ recommends using agreements for high-risk college students prescribed stimulant medications. Red flags for misuse include signs of active substance use (eg, intoxication, a pattern of “lost” prescriptions, and doctor-shopping).²⁷

The effectiveness in reducing risk of misuse in the adult ADHD population has not yet been investigated. Nonetheless, a method of communicating the seriousness of stimulant misuse to adult patients is essential to ADHD care.

STAYING ON TRACK

In the clinical setting, treatment response is measured not just by symptom reduction, but also by functional improvement. Thus, clinicians and patients must set functional goals whenever possible.²⁷ Successful progress toward these goals justifies continuation of therapy, whereas lack of improvement signals the need to reconsider stimulant therapy.²⁷

MONITORING AND DOCUMENTATION

Adults with ADHD present with varying levels of functional impairment and comorbidities, which may require different levels of monitoring.³⁰ Not all patients with ADHD respond optimally to stimulant medications or tolerate them well.^31,32 Hence, monitoring parameters for therapeutic change and adverse outcomes are important in that they guide the alteration or even discontinuation of pharmacotherapy.^4,6,14

Documenting the decision-making process to continue stimulant medications under certain circumstances is also essential. Documentation should include discussion of goals and expectations, risks and benefits, and alternatives to stimulant use.

In adults, risk of stimulant medication misuse adds a new layer of complexity to monitoring.^13,14 Adults may get multiple prescriptions from multiple providers, seek early refills, fill prescriptions at different pharmacies, or alter formulations. Many states track stimulant prescription use, and prescribers can use this information to determine if patients are refilling their prescriptions appropriately or obtaining stimulants from more than one provider.

Although these monitoring strategies are useful,⁶ it is prudent to structure the level of monitoring according to the patient’s risk of adverse events or medication misuse.^14,27 Gourlay and Heit¹⁵ proposed the following “four-A” mnemonic for four domains to be explored at each visit in patients receiving pain medicine. This mnemonic can be applied to adult ADHD patients to more accurately monitor the patient throughout treatment.

THE ‘FOUR-A’ MNEMONIC

ADHD symptoms

Several ADHD scales can be used to track symptom changes over time.³³ However, these self-report scales may be subject to positive illusory bias, a phenomenon observed in individuals with ADHD in which they tend to overrate their functioning,³⁴ which may limit the accuracy of self-report scales.³⁵

Activities of daily living

Since patients with ADHD tend to overrate their functioning in various aspects of living, collateral information should be gathered to corroborate patient self-reports whenever possible.

Adverse events

Blood pressure, heart rate, and weight should be assessed at baseline and monitored during stimulant treatment. Other symptoms to monitor include gastrointestinal distress, headache, aggression, depression, appetite, and sleeping habits.^4,6 More intensive monitoring (eg, electrocardiography) may be indicated for those with hypertension and cardiovascular risk factors.

Aberrant behavior

Monitoring for misuse and diversion of stimulant medications is essential, as ADHD itself is a risk factor for addiction.^20,21 Pill counts, prescription monitoring programs, urine drug screens, and collateral informants have all been proposed but not studied in monitoring for the misuse of stimulant medications.²⁷ Before prescribing, it is prudent to check the prescription monitoring program, get a urine drug screen, and discuss any positive findings with the patient.^36,37

Short-acting stimulant medications are the most likely to be abused

Treatment agreements ensure that patients are aware of the consequences of misuse and allow the clinician to reference prior discussion when terminating treatment with stimulants.

LIVES CAN BE ENHANCED

ADHD is a common disorder that arises in childhood and can persist throughout life. Adults with untreated ADHD are at risk of severe impairments in various domains of functioning. Stimulant medications are an effective treatment but may be diverted into the street market. Using the universal-precautions model may reduce the risks of both nontreatment of ADHD and misuse of stimulants.

Accordingly, clinicians need to confirm the ADHD diagnosis, assess comorbidities, estimate risk of misuse, and provide informed consent prior to prescribing. Subsequent monitoring should involve the use of treatment agreements and evaluating treatment response, paying particular attention to ADHD symptom control but also to level of function, adverse effects, and aberrant behavior.

With these principles in mind, clinicians can address the risks of misuse and potentially enhance the lives of people who may have been suffering substantially due to lack of appropriate care.

Children are not the only people affected by attention-deficit/hyperactivity disorder (ADHD). Characterized by high levels of inattention, overactivity, and impulsivity, ADHD affects 5% of school-aged children, but also 4% of adults.^1–3 Adults with untreated ADHD are likely to develop serious psychosocial problems that manifest as unemployment, arrests, divorce, underachievement, and psychiatric comorbidities.^4,5

However, many clinicians are reluctant to manage adults with ADHD, partly because of concerns about misuse of the stimulant drugs they must prescribe to treat it.

Here, we outline an approach whereby clinicians can diagnose and treat adult ADHD while taking “universal precautions” to discourage misuse of the medications involved.

RECOGNIZING ADHD IN ADULTS

ADHD is characterized by developmentally inappropriate levels of inattention, impulsiveness, and hyperactivity that arise in childhood and result in impairments that often persist.

The presentation of ADHD in adults may be influenced by the longevity of their ADHD, associated sequelae (eg, low self-esteem and interpersonal, educational, and occupational difficulties), and comorbid disorders.⁶ There are neither reliable biomarkers nor neuropsychological tests for diagnosis, and persons with ADHD typically have a complex presentation with at least one comorbidity.^6,7

In patients diagnosed in childhood, difficulties with organization as well as initiating, maintaining, and completing tasks become more prominent in adulthood and hyperactivity tends to subside. Adult impulsivity may present as edginess, shopping sprees, quitting jobs, and risky behaviors.⁶

Overall, the clinical manifestations of ADHD in adolescents and adults include inattention, difficulties with task completion, disorganization, and executive dysfunction—all skills critical to managing the various roles of adult life.

OBSTACLES TO EFFECTIVE TREATMENT

In the past, ADHD treatment was routinely discontinued during adolescence, as it was unclear whether adults still had significant symptoms or benefited from treatment.^8,9 Now, available ADHD guidelines suggest that children and adults who respond to pharmacotherapy should continue it for as long as it remains effective. In this context, there is increasing recognition of adult ADHD as a valid and treatable disorder.¹⁰

Adults with ADHD tend to lack critical skills to manage the various roles of adult life

One of the challenges clinicians face is the reliability of adult recall of childhood ADHD. A controlled, prospective 16-year follow-up study found that of all adults retrospectively given a diagnosis of childhood ADHD, only 27% actually had the disorder.¹¹ This study suggests that retrospective diagnoses of childhood ADHD made solely on the basis of self-reports are unlikely to be valid.

Another obstacle is that traditional medical education has seldom included training in adult ADHD.^8,12 In a UK study, clinicians felt that they lacked training and knowledge to assess and manage adult ADHD patients.⁹

Even if adult ADHD is recognized, diagnosis is just the first step of care.¹³ These patients require ongoing management and follow-up assessments.

Although practice patterns vary, efforts to encourage doctors to provide adult ADHD care may be hindered by the fact that the gold standard of treatment is stimulant medication.^4,10 Medications approved by the US Food and Drug Administration for adult ADHD include the stimulants lisdexamfetamine, osmotic-release methylphenidate, mixed amphetamine salts extended release, dexmethylphenidate extended release, and the nonstimulant atomoxetine.⁶ While stimulants are generally more efficacious for ADHD symptoms than nonstimulants, they are associated with misuse and diversion.¹⁴

UNIVERSAL PRECAUTIONS: A SIMPLIFIED APPROACH

The universal-precautions approach to prescribing stimulants aims to allay physician concerns and promote appropriate medication use to allow for proper management of this disorder.¹⁵ These precautions, to be applied to all adult ADHD patients for whom stimulants are being considered, include careful diagnosis and consideration of comorbidities, baseline risk stratification, informed consent processes, treatment agreements, periodic reassessments of treatment response, and meticulous documentation.

DIAGNOSIS

A frequently used screening assessment for adult ADHD is the ADHD Rating Scale (ADHD RS), which consists of two subscales for assessing hyperactivity/impulsivity and inattentiveness.¹⁶ ADHD can be classified into one of three subtypes based on symptoms: inattentive, hyperactive, or combined type. Symptoms must persist for at least 6 months for a diagnosis to be made. Other ADHD scales include the Conners Adult ADHD Rating Scales and the Brown Attention-Deficit Disorder Scales.⁴

High scores on screening scales must be interpreted within the clinical context. Clinicians need to ask about ADHD symptoms, establish their presence in various settings, and determine if these symptoms interfere with functioning. A diagnosis of adult ADHD also requires evidence of symptoms beginning in childhood.¹⁷ According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, inattentive or hyperactive-impulsive symptoms must be present before age 12 in two or more settings and interfere with function and development.

Although self-reporting screening tools are helpful, these tests are not reliable for diagnostic purposes, and collateral information is also required.

Neuropsychological testing may detect impairments in persons with ADHD. The most consistently employed neuropsychological tests to evaluate ADHD include the Conners Continuous Performance Test, Stroop Color and Word Test, Trail-making Test, verbal fluency tests, Controlled Oral Word Association Test, and the Weschler Adult Intelligence Scale.⁶

COMORBIDITY

Epidemiologic studies suggest that adults with ADHD develop many psychiatric problems including anxiety, depression, and substance use disorders.^7,16 Table 1 illustrates common comorbidities and their associated prevalence in the ADHD patient.⁷

Comorbid psychiatric disorders may affect the presentation of adult ADHD. For instance, adults with comorbid depression and ADHD are more likely to present with heightened irritability and difficulties concentrating on tasks than those with either condition alone.¹⁸ Similarly, antisocial personality disorder is more common in adults with ADHD.¹⁹ Such patients exhibit stable antisocial behavior (lying, stealing, and aggression) as well as medication misuse.^5,14,19

While these comorbid disorders may obscure the ADHD diagnosis, their recognition is essential to effectively manage adult ADHD. In sum, a careful evaluation of the adult, including elucidating both ADHD and comorbid symptoms, functionality in several domains, and the degree of impairment, should precede initiating pharmacotherapy for adult ADHD.

BASELINE RISK STRATIFICATION: RISK FACTORS FOR STIMULANT MISUSE

After diagnosing ADHD, the prescriber must assess the risk for misuse of stimulant medications.²⁰

One study revealed that nonmedical use of stimulant medications occurred in only 2% of the 4,300 people surveyed.²¹ Among the misusers, 66% had obtained medication from family or friends. Another 34% had stolen medication, and 20% had obtained prescriptions from a physician by falsely reporting symptoms. The study also assessed motivation for misuse. In this sample, 40% of misuse was to enhance performance, 34% was for recreation, and 23% was to stay awake.²¹

Other studies show that misuse of stimulant medications is common among youth in the United States, reporting that 18% of college students use some formulation of prescription stimulants.²²

Still more research suggests that childhood conduct disorder or illicit drug use results in a higher risk of stimulant medication misuse.²⁰ Additional risk factors for misuse include male sex, white ethnicity, upper-class background, Jewish or no religious affiliation, affiliation with a sorority or fraternity, off-campus housing, and a low grade-point average.²³

Table 2 illustrates clinical interventions providers can use, once they have risk-stratified their patients, to monitor for stimulant misuse.

HOW SHOULD THESE RISK FACTORS AFFECT TREATMENT?

Although no formal scoring system exists to help clinicians risk-stratify these patients, the presence of multiple risk factors suggests the need for vigilance.¹⁴ Physicians should prescribe agents with less potential for abuse and monitor these patients more intensely.

Short-acting stimulant medications are the most likely to be abused, as phasic dopamine increase is more reinforcing than therapeutic dopamine release.²⁴ Longer-acting stimulant medications are less likely to be abused, and they provide better symptom relief, as tonic dopamine release maintains a steady state and increases the therapeutic efficacy of these medications.²⁵ For example, methylphenidate extended-release tablets have an osmotic oral controlled-release system and are less likely to be crushed for recreational inhalation.^6,14

Lisdexamfetamine is a prodrug therapeutically inert until converted to d-amphetamine when lysine is cleaved from the molecule. This medication may be a good option for patients at high risk of misuse because it is tamper-resistant. However, it still may be subject to misuse for performance enhancement.^26,27

The nonstimulant atomoxetine is also approved for ADHD, has no abuse potential, and may be particularly useful when anxiety, mood, and substance use disorders co-occur with ADHD.⁶ Rarely, atomoxetine can damage the liver, and liver function tests should be monitored if right upper quadrant pain develops.^4,10

Other nonapproved agents such as bupropion and desipramine also have been used empirically and off-label for ADHD.^4,10

Overall, treatment should be selected according to the risk of misuse of stimulant medication and the patient’s comorbidities.

INFORMED CONSENT

Informed consent may help patients appreciate the risks and benefits of the treatment options and develop realistic expectations about treatment.²⁶ Patients are instructed to take their stimulant medications as prescribed and are informed of the risks of combining stimulants with other substances, particularly those that may interact with stimulants (eg, cocaine) and raise the risk of seizures and cardiovascular complications.

Stimulant medications lead to elevations in blood pressure and heart rate, although  large-scale studies have shown no increase in the rate of serious cardiovascular events when these drugs are used appropriately.⁶ Less serious side effects associated with stimulant medications include insomnia, weight loss, decreased appetite, dry mouth, headache, and rarely, depression and anxiety.⁶

Patients need to be warned about diversion and abuse liability of stimulant medications, as well as alternative treatments.

The nonstimulant atomoxetine has no reinforcing properties but also raises the blood pressure and heart rate.⁶ As with stimulants, these elevations are generally minimal, time-limited, and of minor clinical significance.^4,10 Frequent reasons to prescribe atomoxetine include poor tolerability of stimulants and a history of substance abuse. In addition, women with ADHD and high levels of emotional dysregulation or social anxiety appear to be particularly responsive to atomoxetine.⁶

Another consideration is cognitive behavioral therapy, which can augment the effects of pharmacotherapy.⁴ Cognitive behavioral therapy focuses on time management, prioritization, organization, problem-solving, motivation, and emotional regulation.⁴

Finally, patients also need to understand the possible consequences of nontreatment.⁵ Adults with untreated ADHD have high rates of academic and occupational difficulties, anti-social behaviors, and other forms of psychosocial adversity.^4,5

Overall, this process should involve discussing risks and benefits of treatment options with the patient and promoting joint decision-making.

TREATMENT AGREEMENTS

Stimulant medications are classified by the US Drug Enforcement Administration as schedule II substances due to their abuse potential.²⁰

It is important to inform patients of the addictive nature of the medication and to instruct them on how to store stimulants safely.²⁷ Patients need to know that giving away or selling these medications is illegal.²⁷

After diagnosing adult ADHD, assess the risk for misuse of stimulant medications

Treatment agreements establish rules for prescribing and are signed by the patient before initiating therapy.^28,29 Patients are expected to attend all of their appointments, receive their prescriptions from one doctor, and obtain their medication from one pharmacy. These agreements may also require patients to submit to monitoring with random urine drug screens.²⁹ Overall, they underscore the need for patients to follow a treatment plan in order to continue therapy with controlled substances.²⁹

Manning²⁷ recommends using agreements for high-risk college students prescribed stimulant medications. Red flags for misuse include signs of active substance use (eg, intoxication, a pattern of “lost” prescriptions, and doctor-shopping).²⁷

The effectiveness in reducing risk of misuse in the adult ADHD population has not yet been investigated. Nonetheless, a method of communicating the seriousness of stimulant misuse to adult patients is essential to ADHD care.

STAYING ON TRACK

In the clinical setting, treatment response is measured not just by symptom reduction, but also by functional improvement. Thus, clinicians and patients must set functional goals whenever possible.²⁷ Successful progress toward these goals justifies continuation of therapy, whereas lack of improvement signals the need to reconsider stimulant therapy.²⁷

MONITORING AND DOCUMENTATION

Adults with ADHD present with varying levels of functional impairment and comorbidities, which may require different levels of monitoring.³⁰ Not all patients with ADHD respond optimally to stimulant medications or tolerate them well.^31,32 Hence, monitoring parameters for therapeutic change and adverse outcomes are important in that they guide the alteration or even discontinuation of pharmacotherapy.^4,6,14

Documenting the decision-making process to continue stimulant medications under certain circumstances is also essential. Documentation should include discussion of goals and expectations, risks and benefits, and alternatives to stimulant use.

In adults, risk of stimulant medication misuse adds a new layer of complexity to monitoring.^13,14 Adults may get multiple prescriptions from multiple providers, seek early refills, fill prescriptions at different pharmacies, or alter formulations. Many states track stimulant prescription use, and prescribers can use this information to determine if patients are refilling their prescriptions appropriately or obtaining stimulants from more than one provider.

Although these monitoring strategies are useful,⁶ it is prudent to structure the level of monitoring according to the patient’s risk of adverse events or medication misuse.^14,27 Gourlay and Heit¹⁵ proposed the following “four-A” mnemonic for four domains to be explored at each visit in patients receiving pain medicine. This mnemonic can be applied to adult ADHD patients to more accurately monitor the patient throughout treatment.

THE ‘FOUR-A’ MNEMONIC

ADHD symptoms

Several ADHD scales can be used to track symptom changes over time.³³ However, these self-report scales may be subject to positive illusory bias, a phenomenon observed in individuals with ADHD in which they tend to overrate their functioning,³⁴ which may limit the accuracy of self-report scales.³⁵

Activities of daily living

Since patients with ADHD tend to overrate their functioning in various aspects of living, collateral information should be gathered to corroborate patient self-reports whenever possible.

Adverse events

Blood pressure, heart rate, and weight should be assessed at baseline and monitored during stimulant treatment. Other symptoms to monitor include gastrointestinal distress, headache, aggression, depression, appetite, and sleeping habits.^4,6 More intensive monitoring (eg, electrocardiography) may be indicated for those with hypertension and cardiovascular risk factors.

Aberrant behavior

Monitoring for misuse and diversion of stimulant medications is essential, as ADHD itself is a risk factor for addiction.^20,21 Pill counts, prescription monitoring programs, urine drug screens, and collateral informants have all been proposed but not studied in monitoring for the misuse of stimulant medications.²⁷ Before prescribing, it is prudent to check the prescription monitoring program, get a urine drug screen, and discuss any positive findings with the patient.^36,37

Short-acting stimulant medications are the most likely to be abused

Treatment agreements ensure that patients are aware of the consequences of misuse and allow the clinician to reference prior discussion when terminating treatment with stimulants.

LIVES CAN BE ENHANCED

ADHD is a common disorder that arises in childhood and can persist throughout life. Adults with untreated ADHD are at risk of severe impairments in various domains of functioning. Stimulant medications are an effective treatment but may be diverted into the street market. Using the universal-precautions model may reduce the risks of both nontreatment of ADHD and misuse of stimulants.

Accordingly, clinicians need to confirm the ADHD diagnosis, assess comorbidities, estimate risk of misuse, and provide informed consent prior to prescribing. Subsequent monitoring should involve the use of treatment agreements and evaluating treatment response, paying particular attention to ADHD symptom control but also to level of function, adverse effects, and aberrant behavior.

With these principles in mind, clinicians can address the risks of misuse and potentially enhance the lives of people who may have been suffering substantially due to lack of appropriate care.

Children are not the only people affected by attention-deficit/hyperactivity disorder (ADHD). Characterized by high levels of inattention, overactivity, and impulsivity, ADHD affects 5% of school-aged children, but also 4% of adults.^1–3 Adults with untreated ADHD are likely to develop serious psychosocial problems that manifest as unemployment, arrests, divorce, underachievement, and psychiatric comorbidities.^4,5

However, many clinicians are reluctant to manage adults with ADHD, partly because of concerns about misuse of the stimulant drugs they must prescribe to treat it.

Here, we outline an approach whereby clinicians can diagnose and treat adult ADHD while taking “universal precautions” to discourage misuse of the medications involved.

RECOGNIZING ADHD IN ADULTS

ADHD is characterized by developmentally inappropriate levels of inattention, impulsiveness, and hyperactivity that arise in childhood and result in impairments that often persist.

The presentation of ADHD in adults may be influenced by the longevity of their ADHD, associated sequelae (eg, low self-esteem and interpersonal, educational, and occupational difficulties), and comorbid disorders.⁶ There are neither reliable biomarkers nor neuropsychological tests for diagnosis, and persons with ADHD typically have a complex presentation with at least one comorbidity.^6,7

In patients diagnosed in childhood, difficulties with organization as well as initiating, maintaining, and completing tasks become more prominent in adulthood and hyperactivity tends to subside. Adult impulsivity may present as edginess, shopping sprees, quitting jobs, and risky behaviors.⁶

Overall, the clinical manifestations of ADHD in adolescents and adults include inattention, difficulties with task completion, disorganization, and executive dysfunction—all skills critical to managing the various roles of adult life.

OBSTACLES TO EFFECTIVE TREATMENT

In the past, ADHD treatment was routinely discontinued during adolescence, as it was unclear whether adults still had significant symptoms or benefited from treatment.^8,9 Now, available ADHD guidelines suggest that children and adults who respond to pharmacotherapy should continue it for as long as it remains effective. In this context, there is increasing recognition of adult ADHD as a valid and treatable disorder.¹⁰

Adults with ADHD tend to lack critical skills to manage the various roles of adult life

One of the challenges clinicians face is the reliability of adult recall of childhood ADHD. A controlled, prospective 16-year follow-up study found that of all adults retrospectively given a diagnosis of childhood ADHD, only 27% actually had the disorder.¹¹ This study suggests that retrospective diagnoses of childhood ADHD made solely on the basis of self-reports are unlikely to be valid.

Another obstacle is that traditional medical education has seldom included training in adult ADHD.^8,12 In a UK study, clinicians felt that they lacked training and knowledge to assess and manage adult ADHD patients.⁹

Even if adult ADHD is recognized, diagnosis is just the first step of care.¹³ These patients require ongoing management and follow-up assessments.

Although practice patterns vary, efforts to encourage doctors to provide adult ADHD care may be hindered by the fact that the gold standard of treatment is stimulant medication.^4,10 Medications approved by the US Food and Drug Administration for adult ADHD include the stimulants lisdexamfetamine, osmotic-release methylphenidate, mixed amphetamine salts extended release, dexmethylphenidate extended release, and the nonstimulant atomoxetine.⁶ While stimulants are generally more efficacious for ADHD symptoms than nonstimulants, they are associated with misuse and diversion.¹⁴

UNIVERSAL PRECAUTIONS: A SIMPLIFIED APPROACH

The universal-precautions approach to prescribing stimulants aims to allay physician concerns and promote appropriate medication use to allow for proper management of this disorder.¹⁵ These precautions, to be applied to all adult ADHD patients for whom stimulants are being considered, include careful diagnosis and consideration of comorbidities, baseline risk stratification, informed consent processes, treatment agreements, periodic reassessments of treatment response, and meticulous documentation.

DIAGNOSIS

A frequently used screening assessment for adult ADHD is the ADHD Rating Scale (ADHD RS), which consists of two subscales for assessing hyperactivity/impulsivity and inattentiveness.¹⁶ ADHD can be classified into one of three subtypes based on symptoms: inattentive, hyperactive, or combined type. Symptoms must persist for at least 6 months for a diagnosis to be made. Other ADHD scales include the Conners Adult ADHD Rating Scales and the Brown Attention-Deficit Disorder Scales.⁴

High scores on screening scales must be interpreted within the clinical context. Clinicians need to ask about ADHD symptoms, establish their presence in various settings, and determine if these symptoms interfere with functioning. A diagnosis of adult ADHD also requires evidence of symptoms beginning in childhood.¹⁷ According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, inattentive or hyperactive-impulsive symptoms must be present before age 12 in two or more settings and interfere with function and development.

Although self-reporting screening tools are helpful, these tests are not reliable for diagnostic purposes, and collateral information is also required.

Neuropsychological testing may detect impairments in persons with ADHD. The most consistently employed neuropsychological tests to evaluate ADHD include the Conners Continuous Performance Test, Stroop Color and Word Test, Trail-making Test, verbal fluency tests, Controlled Oral Word Association Test, and the Weschler Adult Intelligence Scale.⁶

COMORBIDITY

Epidemiologic studies suggest that adults with ADHD develop many psychiatric problems including anxiety, depression, and substance use disorders.^7,16 Table 1 illustrates common comorbidities and their associated prevalence in the ADHD patient.⁷

Comorbid psychiatric disorders may affect the presentation of adult ADHD. For instance, adults with comorbid depression and ADHD are more likely to present with heightened irritability and difficulties concentrating on tasks than those with either condition alone.¹⁸ Similarly, antisocial personality disorder is more common in adults with ADHD.¹⁹ Such patients exhibit stable antisocial behavior (lying, stealing, and aggression) as well as medication misuse.^5,14,19

While these comorbid disorders may obscure the ADHD diagnosis, their recognition is essential to effectively manage adult ADHD. In sum, a careful evaluation of the adult, including elucidating both ADHD and comorbid symptoms, functionality in several domains, and the degree of impairment, should precede initiating pharmacotherapy for adult ADHD.

BASELINE RISK STRATIFICATION: RISK FACTORS FOR STIMULANT MISUSE

After diagnosing ADHD, the prescriber must assess the risk for misuse of stimulant medications.²⁰

One study revealed that nonmedical use of stimulant medications occurred in only 2% of the 4,300 people surveyed.²¹ Among the misusers, 66% had obtained medication from family or friends. Another 34% had stolen medication, and 20% had obtained prescriptions from a physician by falsely reporting symptoms. The study also assessed motivation for misuse. In this sample, 40% of misuse was to enhance performance, 34% was for recreation, and 23% was to stay awake.²¹

Other studies show that misuse of stimulant medications is common among youth in the United States, reporting that 18% of college students use some formulation of prescription stimulants.²²

Still more research suggests that childhood conduct disorder or illicit drug use results in a higher risk of stimulant medication misuse.²⁰ Additional risk factors for misuse include male sex, white ethnicity, upper-class background, Jewish or no religious affiliation, affiliation with a sorority or fraternity, off-campus housing, and a low grade-point average.²³

Table 2 illustrates clinical interventions providers can use, once they have risk-stratified their patients, to monitor for stimulant misuse.

HOW SHOULD THESE RISK FACTORS AFFECT TREATMENT?

Although no formal scoring system exists to help clinicians risk-stratify these patients, the presence of multiple risk factors suggests the need for vigilance.¹⁴ Physicians should prescribe agents with less potential for abuse and monitor these patients more intensely.

Short-acting stimulant medications are the most likely to be abused, as phasic dopamine increase is more reinforcing than therapeutic dopamine release.²⁴ Longer-acting stimulant medications are less likely to be abused, and they provide better symptom relief, as tonic dopamine release maintains a steady state and increases the therapeutic efficacy of these medications.²⁵ For example, methylphenidate extended-release tablets have an osmotic oral controlled-release system and are less likely to be crushed for recreational inhalation.^6,14

Lisdexamfetamine is a prodrug therapeutically inert until converted to d-amphetamine when lysine is cleaved from the molecule. This medication may be a good option for patients at high risk of misuse because it is tamper-resistant. However, it still may be subject to misuse for performance enhancement.^26,27

The nonstimulant atomoxetine is also approved for ADHD, has no abuse potential, and may be particularly useful when anxiety, mood, and substance use disorders co-occur with ADHD.⁶ Rarely, atomoxetine can damage the liver, and liver function tests should be monitored if right upper quadrant pain develops.^4,10

Other nonapproved agents such as bupropion and desipramine also have been used empirically and off-label for ADHD.^4,10

Overall, treatment should be selected according to the risk of misuse of stimulant medication and the patient’s comorbidities.

INFORMED CONSENT

Informed consent may help patients appreciate the risks and benefits of the treatment options and develop realistic expectations about treatment.²⁶ Patients are instructed to take their stimulant medications as prescribed and are informed of the risks of combining stimulants with other substances, particularly those that may interact with stimulants (eg, cocaine) and raise the risk of seizures and cardiovascular complications.

Stimulant medications lead to elevations in blood pressure and heart rate, although  large-scale studies have shown no increase in the rate of serious cardiovascular events when these drugs are used appropriately.⁶ Less serious side effects associated with stimulant medications include insomnia, weight loss, decreased appetite, dry mouth, headache, and rarely, depression and anxiety.⁶

Patients need to be warned about diversion and abuse liability of stimulant medications, as well as alternative treatments.

The nonstimulant atomoxetine has no reinforcing properties but also raises the blood pressure and heart rate.⁶ As with stimulants, these elevations are generally minimal, time-limited, and of minor clinical significance.^4,10 Frequent reasons to prescribe atomoxetine include poor tolerability of stimulants and a history of substance abuse. In addition, women with ADHD and high levels of emotional dysregulation or social anxiety appear to be particularly responsive to atomoxetine.⁶

Another consideration is cognitive behavioral therapy, which can augment the effects of pharmacotherapy.⁴ Cognitive behavioral therapy focuses on time management, prioritization, organization, problem-solving, motivation, and emotional regulation.⁴

Finally, patients also need to understand the possible consequences of nontreatment.⁵ Adults with untreated ADHD have high rates of academic and occupational difficulties, anti-social behaviors, and other forms of psychosocial adversity.^4,5

Overall, this process should involve discussing risks and benefits of treatment options with the patient and promoting joint decision-making.

TREATMENT AGREEMENTS

Stimulant medications are classified by the US Drug Enforcement Administration as schedule II substances due to their abuse potential.²⁰

It is important to inform patients of the addictive nature of the medication and to instruct them on how to store stimulants safely.²⁷ Patients need to know that giving away or selling these medications is illegal.²⁷

After diagnosing adult ADHD, assess the risk for misuse of stimulant medications

Treatment agreements establish rules for prescribing and are signed by the patient before initiating therapy.^28,29 Patients are expected to attend all of their appointments, receive their prescriptions from one doctor, and obtain their medication from one pharmacy. These agreements may also require patients to submit to monitoring with random urine drug screens.²⁹ Overall, they underscore the need for patients to follow a treatment plan in order to continue therapy with controlled substances.²⁹

Manning²⁷ recommends using agreements for high-risk college students prescribed stimulant medications. Red flags for misuse include signs of active substance use (eg, intoxication, a pattern of “lost” prescriptions, and doctor-shopping).²⁷

The effectiveness in reducing risk of misuse in the adult ADHD population has not yet been investigated. Nonetheless, a method of communicating the seriousness of stimulant misuse to adult patients is essential to ADHD care.

STAYING ON TRACK

In the clinical setting, treatment response is measured not just by symptom reduction, but also by functional improvement. Thus, clinicians and patients must set functional goals whenever possible.²⁷ Successful progress toward these goals justifies continuation of therapy, whereas lack of improvement signals the need to reconsider stimulant therapy.²⁷

MONITORING AND DOCUMENTATION

Adults with ADHD present with varying levels of functional impairment and comorbidities, which may require different levels of monitoring.³⁰ Not all patients with ADHD respond optimally to stimulant medications or tolerate them well.^31,32 Hence, monitoring parameters for therapeutic change and adverse outcomes are important in that they guide the alteration or even discontinuation of pharmacotherapy.^4,6,14

Documenting the decision-making process to continue stimulant medications under certain circumstances is also essential. Documentation should include discussion of goals and expectations, risks and benefits, and alternatives to stimulant use.

In adults, risk of stimulant medication misuse adds a new layer of complexity to monitoring.^13,14 Adults may get multiple prescriptions from multiple providers, seek early refills, fill prescriptions at different pharmacies, or alter formulations. Many states track stimulant prescription use, and prescribers can use this information to determine if patients are refilling their prescriptions appropriately or obtaining stimulants from more than one provider.

Although these monitoring strategies are useful,⁶ it is prudent to structure the level of monitoring according to the patient’s risk of adverse events or medication misuse.^14,27 Gourlay and Heit¹⁵ proposed the following “four-A” mnemonic for four domains to be explored at each visit in patients receiving pain medicine. This mnemonic can be applied to adult ADHD patients to more accurately monitor the patient throughout treatment.

THE ‘FOUR-A’ MNEMONIC

ADHD symptoms

Several ADHD scales can be used to track symptom changes over time.³³ However, these self-report scales may be subject to positive illusory bias, a phenomenon observed in individuals with ADHD in which they tend to overrate their functioning,³⁴ which may limit the accuracy of self-report scales.³⁵

Activities of daily living

Since patients with ADHD tend to overrate their functioning in various aspects of living, collateral information should be gathered to corroborate patient self-reports whenever possible.

Adverse events

Blood pressure, heart rate, and weight should be assessed at baseline and monitored during stimulant treatment. Other symptoms to monitor include gastrointestinal distress, headache, aggression, depression, appetite, and sleeping habits.^4,6 More intensive monitoring (eg, electrocardiography) may be indicated for those with hypertension and cardiovascular risk factors.

Aberrant behavior

Monitoring for misuse and diversion of stimulant medications is essential, as ADHD itself is a risk factor for addiction.^20,21 Pill counts, prescription monitoring programs, urine drug screens, and collateral informants have all been proposed but not studied in monitoring for the misuse of stimulant medications.²⁷ Before prescribing, it is prudent to check the prescription monitoring program, get a urine drug screen, and discuss any positive findings with the patient.^36,37

Short-acting stimulant medications are the most likely to be abused

Treatment agreements ensure that patients are aware of the consequences of misuse and allow the clinician to reference prior discussion when terminating treatment with stimulants.

LIVES CAN BE ENHANCED

ADHD is a common disorder that arises in childhood and can persist throughout life. Adults with untreated ADHD are at risk of severe impairments in various domains of functioning. Stimulant medications are an effective treatment but may be diverted into the street market. Using the universal-precautions model may reduce the risks of both nontreatment of ADHD and misuse of stimulants.

Accordingly, clinicians need to confirm the ADHD diagnosis, assess comorbidities, estimate risk of misuse, and provide informed consent prior to prescribing. Subsequent monitoring should involve the use of treatment agreements and evaluating treatment response, paying particular attention to ADHD symptom control but also to level of function, adverse effects, and aberrant behavior.

With these principles in mind, clinicians can address the risks of misuse and potentially enhance the lives of people who may have been suffering substantially due to lack of appropriate care.

Wounds that fail to heal become more than mere skin lesions. Pain, malodor, and the accompanying psychological distress often complicate nonhealing wounds and impair quality of life.¹ Management of malodor requires perseverance, sensitivity, and familiarity with tools and procedures that range from surgical debridement to medical-grade honey.

Chronic, nonhealing wounds are defined as persisting for more than 6 months.² These lesions are incapable of undergoing anatomic and functional repair on their own. Commonly encountered nonhealing wounds include pressure ulcers, venous stasis ulcers, arterial insufficiency ulcers, and malignant cutaneous wounds.

Typically, the patient with a nonhealing wound is frail, debilitated, medically complex, and often faced with one or more life-limiting illnesses. Complete wound healing may therefore be unrealistic, and optimal wound management becomes the goal of care.^3,4

Healthcare providers encounter nonhealing wounds in varied settings—acute inpatient, outpatient, long-term, and home care. For instance, in the home care setting, a study of 383 patients enrolled in hospice found that 35% had skin ulcers and wounds.³ Half of those affected had pressure ulcers, 20% had ischemic ulcers, and 30% had other skin disorders such as stasis ulcers, burns, skin tears, and tumors. A larger study, also in hospice patients, found that 26% had pressure ulcers and 10% more developed them within 6 months.⁵

While pressure ulcers are the most common nonhealing wounds, malignant or fungating wounds are found in 5% to 10% of patients with metastatic disease, usually with cancers of the breast, head, and neck.⁶

The three major causes of wound malodor are slough, infection, and exudate

Maximizing wound care provides comfort, relieves suffering, and promotes quality of life.^3,7 To achieve these goals, clinicians must be familiar with strategies to manage complications associated with nonhealing wounds such as pain, malodor, and psychosocial adverse effects. Of these complications, malodor has been pointed out by both patients and caregivers as the most distressing.⁸

This article focuses on wound malodor, discusses the processes that cause wounds to emit an offensive smell, and outlines a comprehensive management approach.

MRS. A., AGE 61, WITH STAGE IV BREAST CANCER

Mrs. A., 61 years old, had a fungating mass in her left breast, which began as a small nodule and progressively enlarged to deform her breast over several months. Her oncologist subsequently staged the extent of her cancer as stage IV after workup revealed lung metastasis. Mrs. A. and her family decided to forgo cancer treatment, including radiotherapy, and to transition to hospice care after discussions with the oncologist.

Mrs. A. lived at home with her husband. Her daughter and three grandchildren all lived nearby.

When her hospice physician arrived at her home to meet her, a strong, pungent, and nauseating smell greeted him as he entered her bedroom. The patient said that for the past few months she had been increasingly distressed by the revolting odor. She rarely left home and had been ashamed to have people visit her, including her family.

On examination, the physician noticed a large fungating mass with yellowish discharge and necrotic tissue in her left breast. In addition to mild pain, she was immensely bothered by the strong odor coming from her breast.

THE IMPACT OF MALODOR

As seen in the case of Mrs. A., malodor has grave effects, both physical and psychological. Patients experience impaired or socially unacceptable body image, social rejection, personal shame, and embarrassment.^9,10 Feelings of fear, anxiety, and depression are common. If left uncontrolled, malodor results in social isolation, reluctance to engage in social activities, diminished appetite, and nausea. In addition, malodor is a constant reminder of patients’ pain and cancer, and it results in further suffering.¹¹

Reactions of family members and caregivers can worsen the situation.^9,12 Expressions of revulsion limit contact and inhibit intimacy, especially near the end of life. Caregivers are often frustrated and distressed over their inability to control the malodor. The environment becomes uninhabitable, and the malodor can permeate clothing, furniture, and living quarters.

Managing malodor can be emotionally draining, physically daunting, and frustrating for healthcare professionals, as several methods are usually employed, often in a trial-and-error approach, to achieve an acceptable degree of odor control. In addition, clinicians must face the challenge of treating malodorous wounds at very close distance without reacting in a way that offends or alarms patients and family members.¹³

MALODOR PRODUCTION: WHERE IS THAT SMELL COMING FROM?

All wounds can produce an odor.¹⁴ Wounds that are expected to heal typically emit a faint but not unpleasant odor, akin to fresh blood. Wounds colonized by Pseudomonas aeruginosa produce a fruity or grapelike odor that is tolerable. Malodor occurs with wounds infected by other gram-negative organisms or anaerobic bacteria.¹⁵ Similarly, wounds covered by necrotic tissue smell like decaying flesh.

Three major causes

The three major causes of wound malodor are slough, infection, and exudate (Figure 1).

Slough is dead or necrotic tissue, usually resulting from vascular compromise. Arterial ulcers, pressure ulcers, and malignant wounds all form slough from capillary occlusion, subsequent ischemia, and tissue necrosis.

Infection. Devitalized tissue, an ideal medium in which bacteria thrive, becomes the source of infection. Anaerobic bacteria are usually implicated in malodor. These include Bacteroides fragilis, Bacteroides prevotella, Clostridium perfringens, and Fusobacterium nucleatum.^16,17 Anaerobic organisms produce putrescine and cadaverine, which are largely responsible for the offensive odor.^16,18 Volatile fatty acids such as propionic, butyric, isovaleric, and valeric acid are formed from lipid catabolism by anaerobes and add to malodor.¹⁷ Aerobic bacteria such as Proteus, Klebsiella, and Pseudomonas species supercolonize necrotic tissue as well and contribute to malodor.^17,18

Exudate. Since nonhealing wounds undergo repeated cycles of inflammation, infection, and necrosis, accumulation of exudate becomes inevitable. Exudate typically is a pus-like fluid containing serum, fibrin, and white blood cells, which leak from blood vessels. In addition, bacteria that colonize chronic wounds filled with necrotic tissue activate proteases that degrade and liquefy dead tissue, thereby forming extensive amounts of exudate.¹⁹

Apart from slough, infection, and exudate, poor general hygiene and dressings left on for too long may contribute to malodor.¹⁶ Moisture-retentive dressings such as hydrocolloids leave an odor after removal. Dressings that liquefy upon contact with the wound surface leave a pus-like, potentially malodorous material.

MALODOR ASSESSMENT: DO YOU SMELL SOMETHING?

Various ways to document wound malodor can prove useful in guiding assessment and treatment. Descriptions such as “foul,” “putrid,” “fishy,” or “filled the room” vividly portray the initial presentation. A 10-point numerical scale similar to a numerical pain scale or a visual analogue scale can be used as a subjective measure.

Other grading methods, which to the authors’ knowledge are not validated, may be helpful. In a study that focused on patients suffering from malodorous gynecologic malignancies, von Gruenigen et al²⁰ used a 0-to-3 scale:

• 0 Absent
• 1 Not offensive
• 2 Offensive but tolerable
• 3 Offensive and intolerable.

A scale often adapted by other authors was devised by Baker and Haig,²¹ which clearly defines four classes:

• 1 Strong—odor is evident upon entering the room (6 to 10 feet from the patient) with the dressing intact
• 2 Moderate—odor is evident upon entering the room with dressing removed
• 3 Slight—odor is evident at close proximity to the patient when the dressing is removed
• 4 No odor—no odor is evident, even at the patient’s bedside with the dressing removed.

COMPREHENSIVE MANAGEMENT: HOW DO WE WIN THE ‘RACE’?

The acronym RACE outlines an approach to dealing with malodor. It stands for removal of necrotic tissue; antibacterials; odor concealers; and education and support (Table 1).

Remove necrotic tissue

An important step in eliminating malodor is to remove necrotic tissue. This starts with debridement, which decreases the incidence of infection and hastens wound closure.^22,23 Table 2 compares the different types of debridement.

Sharp or surgical debridement involves the use of a scalpel or scissors. This type of debridement may increase the risk of bleeding, pain, and malignant cell seeding in fungating wounds.^4,24

Enzymatic debridement employs chemicals with proteolytic action (eg, collagenase) to digest extracellular proteins in wounds.^18,25

Mechanical debridement involves aggressive therapies such as forceful irrigation and hydrotherapy, which may fail to discriminate between necrotic and viable tissues.^18,26

Biological debridement using maggots, which ingest bacteria and devitalized tissue, may cause increased wound bleeding and may be unacceptable for patients and families.^24,27

Autolytic debridement is often recommended, particularly if complete healing is not the primary goal.^17,24,28,29 Autolysis uses proteolytic enzymes and phagocytic cells present in the wound bed and wound fluid to clear devitalized tissue. It is easy, inexpensive, noninvasive, and painless,⁴ and it requires less frequent dressing changes relative to standard dressing or wet-to-dry dressing.

Autolytic debridement is commonly accomplished using hydrocolloid and hydrogel dressings.^15,29 Hydrocolloids are adhesive, occlusive, and conformable dressings that are suitable for wounds with low to moderate amounts of exudate. Upon contact with the wound surface, the dressing absorbs the exudate, forms a gel layer, and maintains a moist environment. Hydrocolloids are not recommended for infected wounds or for those with copious exudate as they may lead to maceration around the wound. A disadvantage of hydrocolloid dressings is their tendency to generate brown, often malodorous exudate when removed.

On the other hand, hydrogels in amorphous gel, dressing, sheet, or impregnated gauze form are water-based products that create a moist environment similar to hydrocolloids. Aside from causing minimal trauma to the wound bed when removed, the dressing’s cooling effect may bring some pain relief. Hydrogels are appropriate for dry wounds and for those with minimal exudate.

After debridement, the wound is cleansed and irrigated. A number of cleansers and solutions are available, but normal saline is a cheap alternative. To irrigate, experts recommend an 18- or 20-gauge intravenous catheter attached to a 30- or 60-mL syringe.¹⁵ This technique provides 8 to 15 psi of pressure, enough to cleanse the wound without causing tissue trauma.

Antibacterials and absorption

Antibacterials. Topical antibiotics have several advantages over systemic antibiotics in treating chronic wounds.^30,31 These include a high and sustained concentration of the antimicrobial at the site of infection, limited potential for systemic absorption and toxicity, reduced potential for antibiotic resistance, and drawing of the patient’s and caregiver’s attention to the wound.

Metronidazole is the most widely used topical antibacterial for malodor management. Its efficacy is likely due to the predominant involvement of anaerobic bacteria in foul-smelling wounds. Topical metronidazole is available as a gel and as a cream. A systematic review showed that on average, topical metronidazole was used once daily for 14 consecutive days.¹⁹ The layer of topical metronidazole is typically covered with a nonadherent primary dressing followed by an absorbent secondary dressing.

The best clinical evidence for topical metronidazole consists of case reports and series.^32–35 The largest of these studies was done by Finlay et al, who treated 47 patients with malodorous benign and malignant cutaneous wounds with 0.75% metronidazole gel daily.³² Forty-five (96%) of the patients reported significantly decreased odor by 14 days, as well as decreased pain, discharge, and surrounding cellulitis.

A randomized, placebo-controlled trial conducted by Bale et al had equivocal findings.⁹ All 41 patients who received metronidazole gel reported a decrease in malodor within 3 days of starting it. However, 76% of patients who received placebo also reported malodor control; in the final analysis, no significant difference was noted in the success rate between the two groups.

Metronidazole tablets can be crushed and sprinkled over the wound. As with metronidazole gel or cream, the crushed tablets are applied daily and covered by a primary nonadherent dressing and an absorbent secondary dressing. This off-label use of metronidazole serves as a cheaper alternative to commercially available topical preparations. To our knowledge, there has been no head-to-head trial comparing the two topical strategies.

Systemic metronidazole, often given orally, has been recommended if evidence of deep tissue or systemic infection is noted¹⁵ and in cases of fungating wounds with fistulas invading either the gastrointestinal or genitourinary tracts.¹⁸ Side effects such as nausea, neuropathy, and alcohol intolerance (ie, disulfiram reaction) may occur, which are not seen with topical metronidazole.

Both topical and systemic metronidazole can be used together on a time-limited basis for extensive malodorous wounds, such as fungating malignant wounds or stage IV sacral pressure ulcers.

Other antimicrobial agents used to treat malodor include silver-containing products, iodine-containing topical agents, mupirocin, bacitracin, neomycin, and polymyxin B.

Honey has been used for wound care since the era of the ancient Egyptians

Honey was used for wound care by the ancient Egyptians, and it is still used.³⁶ Its beneficial effects include antimicrobial, debriding, deodorizing, anti-inflammatory, and granulation tissue-stimulating. Honey has even been shown to significantly decrease skin colonization with various kinds of bacteria, including methicillin-resistant Staphylococcus aureus.³⁷ Medical-grade honey is preferred over table honey, as the latter is nonsterile and can contain Clostridium spores, which contaminate the wound.³⁸

Yogurt and buttermilk lower the pH of the wound and control bacterial proliferation to control malodor.^39,40 Either is applied for 10 to 15 minutes after the wound is cleansed and is then washed off thoroughly.

Absorbent dressings are used either over a layer of topical metronidazole and a nonadherent primary dressing or as a primary dressing itself. An absorbent dressing containing activated charcoal is used for rapid improvement, although cost may be prohibitive, especially in developing countries.^13,19 Another type of absorbent dressing, composed of polyester impregnated with sodium chloride, has been found to be useful in malodor control.⁴¹ An important pointer is to maintain a tight seal around the absorbent dressing to prevent leakage of exudate.

Concealers

Aromatics used to conceal malodor include scented candles, incense, fragrant flowers and plants, and air-freshener sprays. When circumstances allow, candles are good options since they conceal malodor by emitting fragrance, and the flame burns off foul-smelling chemicals. Aromatics such as coffee beans, vanilla beans, and cider vinegar can be placed in a pan and left under the patient’s bed or close to it. Drops of peppermint oil or oil of wintergreen can be placed on wound dressings.

Other odor concealers are adsorbent materials that attract and cause ions and molecules to adhere to their surface. Examples are charcoal, baking soda, and cat litter. As with other aromatics, these materials are placed in pans and left under the bed or near the patient.

Aromatics can have disadvantages, as certain scents, especially strong ones, can be nauseating for patients. Some fragrances trigger asthma or skin irritation. Patients and caregivers can be left with an unpleasant association of certain fragrances with malodor by conditioning.^15,17,18

Education and support

Concerns of the patient and family members need to be heard, addressed promptly, and reassessed with each visit, since uncontrolled malodor can be a chief source of caregiver fatigue.

Foremost in formulating a patient- and family-centered malodor management strategy is to commit to controlling malodor as much as possible. Regular follow-up appointments should be made, whether in the office or at home, to check on the patient’s progress and address new and ongoing concerns. Symptoms accompanying malodor, such as pain, bleeding, and sleep disturbance, need to be addressed, as they all affect quality of life.¹ Audience-appropriate educational materials should be made available.²⁶ Online resources that patients and families can explore include the websites of the Wound Ostomy and Continence Nurses Society (www.wocn.org) and the Association for the Advancement of Wound Care (aawconline.org).

Avoid expressing distress at odors in front of or within hearing of patients and families

Healthcare professionals need to be prepared to deal with problems and complications involving patients and family members that may arise in the course of treatment.¹² Problems include the cost and local unavailability of dressing supplies, insurance coverage for dressings and topical agents, lack of assistance at home, and fear of changing dressings. A cardinal rule for healthcare providers is to avoid expressing distress at odors in front of or within hearing of patients and families.

OTHER STRATEGIES: WHAT ELSE CAN WE DO?

Curcumin, the main biologically active compound in the herb turmeric, applied directly to wounds three times daily as an ointment, has been shown to have odor-controlling properties.⁴²

Sugar paste has been reported to control malodor by drawing out exudative and tissue fluid osmotically, and inhibiting bacterial growth.^16,17 Water is mixed with sugar (ie, granulated, caster, or powdered) to form a paste, with additives like glycerin and polyethylene glycol used to alter the consistency. Thick clay-like paste is good for wounds with large cavities, while thin paste is useful for wounds with small or superficial openings. The paste is applied twice daily and is covered by an absorbent dressing.

Pressure relief is vital in managing pressure ulcers.^18,43 Repositioning every 2 hours and using special devices, such as mattress overlays, alternating pressure mattresses, and low air loss mattresses, are frequently employed techniques.

If circumstances permit and when congruent with the patient’s goals of care, intra-arterial chemotherapy and radiotherapy can be contemplated for malignant fungating wounds.^44,45

Other strategies include opening the windows during dressing changes, increasing the frequency of dressing changes, promptly removing used dressings from the house, and ensuring good general hygiene.

CASE RESOLUTION

After telling her that he was committed to control the malodor or, if possible, eliminate it, Mrs. A.’s doctor prepared two lists of materials—one for himself and one for Mrs. A.’s husband. He returned the next day, brought out his supplies, asked Mrs. A. to lie in bed, and invited her husband to assist him.

He cleansed and irrigated the breast lesion with normal saline, making sure to remove as much dead tissue as he could. He applied a layer of metronidazole cream to the wound cavity, then covered it with a nonadherent dressing. He then covered the wound with gauze, sealed the edges with medical adhesive tape, and applied a few drops of oil of wintergreen to the surface. A pan of charcoal briquettes was put under the bed, and a candle with Mrs. A.’s favorite scent was lit by the bedside. The physician then instructed Mrs. A.’s husband to repeat the procedure once daily for 1 week.

After 2 weeks, Mrs. A. and her husband said the foul odor had greatly decreased. She appeared more cheerful and energetic, especially after her grandchildren visited a few days earlier. The physician then instructed the husband to stop using metronidazole cream and to apply a hydrocolloid dressing every 3 days instead. He advised them to continue the rest of the process of applying a few drops of oil of wintergreen on the dressing surface, placing a pan of charcoal briquettes under the bed, and lighting a scented candle by the bedside.

FINISH THE RACE!

Complex nonhealing wounds are encountered across various healthcare settings. Wound malodor is an important component of nonhealing wounds, which adversely affects patients, families, and healthcare providers. Infection, slough, and exudate are the major causes of wound malodor. The essential steps to reduce malodor are to remove necrotic tissue, use antibacterial and odor-absorbing agents, apply appropriate odor “concealers,” educate families, and formulate a patient- and family-centered strategy (Table 1).
 

Acknowledgment: The authors would like to thank Sue Reif, CNP, for her assistance in completing the manuscript.

Wounds that fail to heal become more than mere skin lesions. Pain, malodor, and the accompanying psychological distress often complicate nonhealing wounds and impair quality of life.¹ Management of malodor requires perseverance, sensitivity, and familiarity with tools and procedures that range from surgical debridement to medical-grade honey.

Chronic, nonhealing wounds are defined as persisting for more than 6 months.² These lesions are incapable of undergoing anatomic and functional repair on their own. Commonly encountered nonhealing wounds include pressure ulcers, venous stasis ulcers, arterial insufficiency ulcers, and malignant cutaneous wounds.

Typically, the patient with a nonhealing wound is frail, debilitated, medically complex, and often faced with one or more life-limiting illnesses. Complete wound healing may therefore be unrealistic, and optimal wound management becomes the goal of care.^3,4

Healthcare providers encounter nonhealing wounds in varied settings—acute inpatient, outpatient, long-term, and home care. For instance, in the home care setting, a study of 383 patients enrolled in hospice found that 35% had skin ulcers and wounds.³ Half of those affected had pressure ulcers, 20% had ischemic ulcers, and 30% had other skin disorders such as stasis ulcers, burns, skin tears, and tumors. A larger study, also in hospice patients, found that 26% had pressure ulcers and 10% more developed them within 6 months.⁵

While pressure ulcers are the most common nonhealing wounds, malignant or fungating wounds are found in 5% to 10% of patients with metastatic disease, usually with cancers of the breast, head, and neck.⁶

The three major causes of wound malodor are slough, infection, and exudate

Maximizing wound care provides comfort, relieves suffering, and promotes quality of life.^3,7 To achieve these goals, clinicians must be familiar with strategies to manage complications associated with nonhealing wounds such as pain, malodor, and psychosocial adverse effects. Of these complications, malodor has been pointed out by both patients and caregivers as the most distressing.⁸

This article focuses on wound malodor, discusses the processes that cause wounds to emit an offensive smell, and outlines a comprehensive management approach.

MRS. A., AGE 61, WITH STAGE IV BREAST CANCER

Mrs. A., 61 years old, had a fungating mass in her left breast, which began as a small nodule and progressively enlarged to deform her breast over several months. Her oncologist subsequently staged the extent of her cancer as stage IV after workup revealed lung metastasis. Mrs. A. and her family decided to forgo cancer treatment, including radiotherapy, and to transition to hospice care after discussions with the oncologist.

Mrs. A. lived at home with her husband. Her daughter and three grandchildren all lived nearby.

When her hospice physician arrived at her home to meet her, a strong, pungent, and nauseating smell greeted him as he entered her bedroom. The patient said that for the past few months she had been increasingly distressed by the revolting odor. She rarely left home and had been ashamed to have people visit her, including her family.

On examination, the physician noticed a large fungating mass with yellowish discharge and necrotic tissue in her left breast. In addition to mild pain, she was immensely bothered by the strong odor coming from her breast.

THE IMPACT OF MALODOR

As seen in the case of Mrs. A., malodor has grave effects, both physical and psychological. Patients experience impaired or socially unacceptable body image, social rejection, personal shame, and embarrassment.^9,10 Feelings of fear, anxiety, and depression are common. If left uncontrolled, malodor results in social isolation, reluctance to engage in social activities, diminished appetite, and nausea. In addition, malodor is a constant reminder of patients’ pain and cancer, and it results in further suffering.¹¹

Reactions of family members and caregivers can worsen the situation.^9,12 Expressions of revulsion limit contact and inhibit intimacy, especially near the end of life. Caregivers are often frustrated and distressed over their inability to control the malodor. The environment becomes uninhabitable, and the malodor can permeate clothing, furniture, and living quarters.

Managing malodor can be emotionally draining, physically daunting, and frustrating for healthcare professionals, as several methods are usually employed, often in a trial-and-error approach, to achieve an acceptable degree of odor control. In addition, clinicians must face the challenge of treating malodorous wounds at very close distance without reacting in a way that offends or alarms patients and family members.¹³

MALODOR PRODUCTION: WHERE IS THAT SMELL COMING FROM?

All wounds can produce an odor.¹⁴ Wounds that are expected to heal typically emit a faint but not unpleasant odor, akin to fresh blood. Wounds colonized by Pseudomonas aeruginosa produce a fruity or grapelike odor that is tolerable. Malodor occurs with wounds infected by other gram-negative organisms or anaerobic bacteria.¹⁵ Similarly, wounds covered by necrotic tissue smell like decaying flesh.

Three major causes

The three major causes of wound malodor are slough, infection, and exudate (Figure 1).

Slough is dead or necrotic tissue, usually resulting from vascular compromise. Arterial ulcers, pressure ulcers, and malignant wounds all form slough from capillary occlusion, subsequent ischemia, and tissue necrosis.

Infection. Devitalized tissue, an ideal medium in which bacteria thrive, becomes the source of infection. Anaerobic bacteria are usually implicated in malodor. These include Bacteroides fragilis, Bacteroides prevotella, Clostridium perfringens, and Fusobacterium nucleatum.^16,17 Anaerobic organisms produce putrescine and cadaverine, which are largely responsible for the offensive odor.^16,18 Volatile fatty acids such as propionic, butyric, isovaleric, and valeric acid are formed from lipid catabolism by anaerobes and add to malodor.¹⁷ Aerobic bacteria such as Proteus, Klebsiella, and Pseudomonas species supercolonize necrotic tissue as well and contribute to malodor.^17,18

Exudate. Since nonhealing wounds undergo repeated cycles of inflammation, infection, and necrosis, accumulation of exudate becomes inevitable. Exudate typically is a pus-like fluid containing serum, fibrin, and white blood cells, which leak from blood vessels. In addition, bacteria that colonize chronic wounds filled with necrotic tissue activate proteases that degrade and liquefy dead tissue, thereby forming extensive amounts of exudate.¹⁹

Apart from slough, infection, and exudate, poor general hygiene and dressings left on for too long may contribute to malodor.¹⁶ Moisture-retentive dressings such as hydrocolloids leave an odor after removal. Dressings that liquefy upon contact with the wound surface leave a pus-like, potentially malodorous material.

MALODOR ASSESSMENT: DO YOU SMELL SOMETHING?

Various ways to document wound malodor can prove useful in guiding assessment and treatment. Descriptions such as “foul,” “putrid,” “fishy,” or “filled the room” vividly portray the initial presentation. A 10-point numerical scale similar to a numerical pain scale or a visual analogue scale can be used as a subjective measure.

Other grading methods, which to the authors’ knowledge are not validated, may be helpful. In a study that focused on patients suffering from malodorous gynecologic malignancies, von Gruenigen et al²⁰ used a 0-to-3 scale:

• 0 Absent
• 1 Not offensive
• 2 Offensive but tolerable
• 3 Offensive and intolerable.

A scale often adapted by other authors was devised by Baker and Haig,²¹ which clearly defines four classes:

• 1 Strong—odor is evident upon entering the room (6 to 10 feet from the patient) with the dressing intact
• 2 Moderate—odor is evident upon entering the room with dressing removed
• 3 Slight—odor is evident at close proximity to the patient when the dressing is removed
• 4 No odor—no odor is evident, even at the patient’s bedside with the dressing removed.

COMPREHENSIVE MANAGEMENT: HOW DO WE WIN THE ‘RACE’?

The acronym RACE outlines an approach to dealing with malodor. It stands for removal of necrotic tissue; antibacterials; odor concealers; and education and support (Table 1).

Remove necrotic tissue

An important step in eliminating malodor is to remove necrotic tissue. This starts with debridement, which decreases the incidence of infection and hastens wound closure.^22,23 Table 2 compares the different types of debridement.

Sharp or surgical debridement involves the use of a scalpel or scissors. This type of debridement may increase the risk of bleeding, pain, and malignant cell seeding in fungating wounds.^4,24

Enzymatic debridement employs chemicals with proteolytic action (eg, collagenase) to digest extracellular proteins in wounds.^18,25

Mechanical debridement involves aggressive therapies such as forceful irrigation and hydrotherapy, which may fail to discriminate between necrotic and viable tissues.^18,26

Biological debridement using maggots, which ingest bacteria and devitalized tissue, may cause increased wound bleeding and may be unacceptable for patients and families.^24,27

Autolytic debridement is often recommended, particularly if complete healing is not the primary goal.^17,24,28,29 Autolysis uses proteolytic enzymes and phagocytic cells present in the wound bed and wound fluid to clear devitalized tissue. It is easy, inexpensive, noninvasive, and painless,⁴ and it requires less frequent dressing changes relative to standard dressing or wet-to-dry dressing.

Autolytic debridement is commonly accomplished using hydrocolloid and hydrogel dressings.^15,29 Hydrocolloids are adhesive, occlusive, and conformable dressings that are suitable for wounds with low to moderate amounts of exudate. Upon contact with the wound surface, the dressing absorbs the exudate, forms a gel layer, and maintains a moist environment. Hydrocolloids are not recommended for infected wounds or for those with copious exudate as they may lead to maceration around the wound. A disadvantage of hydrocolloid dressings is their tendency to generate brown, often malodorous exudate when removed.

On the other hand, hydrogels in amorphous gel, dressing, sheet, or impregnated gauze form are water-based products that create a moist environment similar to hydrocolloids. Aside from causing minimal trauma to the wound bed when removed, the dressing’s cooling effect may bring some pain relief. Hydrogels are appropriate for dry wounds and for those with minimal exudate.

After debridement, the wound is cleansed and irrigated. A number of cleansers and solutions are available, but normal saline is a cheap alternative. To irrigate, experts recommend an 18- or 20-gauge intravenous catheter attached to a 30- or 60-mL syringe.¹⁵ This technique provides 8 to 15 psi of pressure, enough to cleanse the wound without causing tissue trauma.

Antibacterials and absorption

Antibacterials. Topical antibiotics have several advantages over systemic antibiotics in treating chronic wounds.^30,31 These include a high and sustained concentration of the antimicrobial at the site of infection, limited potential for systemic absorption and toxicity, reduced potential for antibiotic resistance, and drawing of the patient’s and caregiver’s attention to the wound.

Metronidazole is the most widely used topical antibacterial for malodor management. Its efficacy is likely due to the predominant involvement of anaerobic bacteria in foul-smelling wounds. Topical metronidazole is available as a gel and as a cream. A systematic review showed that on average, topical metronidazole was used once daily for 14 consecutive days.¹⁹ The layer of topical metronidazole is typically covered with a nonadherent primary dressing followed by an absorbent secondary dressing.

The best clinical evidence for topical metronidazole consists of case reports and series.^32–35 The largest of these studies was done by Finlay et al, who treated 47 patients with malodorous benign and malignant cutaneous wounds with 0.75% metronidazole gel daily.³² Forty-five (96%) of the patients reported significantly decreased odor by 14 days, as well as decreased pain, discharge, and surrounding cellulitis.

A randomized, placebo-controlled trial conducted by Bale et al had equivocal findings.⁹ All 41 patients who received metronidazole gel reported a decrease in malodor within 3 days of starting it. However, 76% of patients who received placebo also reported malodor control; in the final analysis, no significant difference was noted in the success rate between the two groups.

Metronidazole tablets can be crushed and sprinkled over the wound. As with metronidazole gel or cream, the crushed tablets are applied daily and covered by a primary nonadherent dressing and an absorbent secondary dressing. This off-label use of metronidazole serves as a cheaper alternative to commercially available topical preparations. To our knowledge, there has been no head-to-head trial comparing the two topical strategies.

Systemic metronidazole, often given orally, has been recommended if evidence of deep tissue or systemic infection is noted¹⁵ and in cases of fungating wounds with fistulas invading either the gastrointestinal or genitourinary tracts.¹⁸ Side effects such as nausea, neuropathy, and alcohol intolerance (ie, disulfiram reaction) may occur, which are not seen with topical metronidazole.

Both topical and systemic metronidazole can be used together on a time-limited basis for extensive malodorous wounds, such as fungating malignant wounds or stage IV sacral pressure ulcers.

Other antimicrobial agents used to treat malodor include silver-containing products, iodine-containing topical agents, mupirocin, bacitracin, neomycin, and polymyxin B.

Honey has been used for wound care since the era of the ancient Egyptians

Honey was used for wound care by the ancient Egyptians, and it is still used.³⁶ Its beneficial effects include antimicrobial, debriding, deodorizing, anti-inflammatory, and granulation tissue-stimulating. Honey has even been shown to significantly decrease skin colonization with various kinds of bacteria, including methicillin-resistant Staphylococcus aureus.³⁷ Medical-grade honey is preferred over table honey, as the latter is nonsterile and can contain Clostridium spores, which contaminate the wound.³⁸

Yogurt and buttermilk lower the pH of the wound and control bacterial proliferation to control malodor.^39,40 Either is applied for 10 to 15 minutes after the wound is cleansed and is then washed off thoroughly.

Absorbent dressings are used either over a layer of topical metronidazole and a nonadherent primary dressing or as a primary dressing itself. An absorbent dressing containing activated charcoal is used for rapid improvement, although cost may be prohibitive, especially in developing countries.^13,19 Another type of absorbent dressing, composed of polyester impregnated with sodium chloride, has been found to be useful in malodor control.⁴¹ An important pointer is to maintain a tight seal around the absorbent dressing to prevent leakage of exudate.

Concealers

Aromatics used to conceal malodor include scented candles, incense, fragrant flowers and plants, and air-freshener sprays. When circumstances allow, candles are good options since they conceal malodor by emitting fragrance, and the flame burns off foul-smelling chemicals. Aromatics such as coffee beans, vanilla beans, and cider vinegar can be placed in a pan and left under the patient’s bed or close to it. Drops of peppermint oil or oil of wintergreen can be placed on wound dressings.

Other odor concealers are adsorbent materials that attract and cause ions and molecules to adhere to their surface. Examples are charcoal, baking soda, and cat litter. As with other aromatics, these materials are placed in pans and left under the bed or near the patient.

Aromatics can have disadvantages, as certain scents, especially strong ones, can be nauseating for patients. Some fragrances trigger asthma or skin irritation. Patients and caregivers can be left with an unpleasant association of certain fragrances with malodor by conditioning.^15,17,18

Education and support

Concerns of the patient and family members need to be heard, addressed promptly, and reassessed with each visit, since uncontrolled malodor can be a chief source of caregiver fatigue.

Foremost in formulating a patient- and family-centered malodor management strategy is to commit to controlling malodor as much as possible. Regular follow-up appointments should be made, whether in the office or at home, to check on the patient’s progress and address new and ongoing concerns. Symptoms accompanying malodor, such as pain, bleeding, and sleep disturbance, need to be addressed, as they all affect quality of life.¹ Audience-appropriate educational materials should be made available.²⁶ Online resources that patients and families can explore include the websites of the Wound Ostomy and Continence Nurses Society (www.wocn.org) and the Association for the Advancement of Wound Care (aawconline.org).

Avoid expressing distress at odors in front of or within hearing of patients and families

Healthcare professionals need to be prepared to deal with problems and complications involving patients and family members that may arise in the course of treatment.¹² Problems include the cost and local unavailability of dressing supplies, insurance coverage for dressings and topical agents, lack of assistance at home, and fear of changing dressings. A cardinal rule for healthcare providers is to avoid expressing distress at odors in front of or within hearing of patients and families.

OTHER STRATEGIES: WHAT ELSE CAN WE DO?

Curcumin, the main biologically active compound in the herb turmeric, applied directly to wounds three times daily as an ointment, has been shown to have odor-controlling properties.⁴²

Sugar paste has been reported to control malodor by drawing out exudative and tissue fluid osmotically, and inhibiting bacterial growth.^16,17 Water is mixed with sugar (ie, granulated, caster, or powdered) to form a paste, with additives like glycerin and polyethylene glycol used to alter the consistency. Thick clay-like paste is good for wounds with large cavities, while thin paste is useful for wounds with small or superficial openings. The paste is applied twice daily and is covered by an absorbent dressing.

Pressure relief is vital in managing pressure ulcers.^18,43 Repositioning every 2 hours and using special devices, such as mattress overlays, alternating pressure mattresses, and low air loss mattresses, are frequently employed techniques.

If circumstances permit and when congruent with the patient’s goals of care, intra-arterial chemotherapy and radiotherapy can be contemplated for malignant fungating wounds.^44,45

Other strategies include opening the windows during dressing changes, increasing the frequency of dressing changes, promptly removing used dressings from the house, and ensuring good general hygiene.

CASE RESOLUTION

After telling her that he was committed to control the malodor or, if possible, eliminate it, Mrs. A.’s doctor prepared two lists of materials—one for himself and one for Mrs. A.’s husband. He returned the next day, brought out his supplies, asked Mrs. A. to lie in bed, and invited her husband to assist him.

He cleansed and irrigated the breast lesion with normal saline, making sure to remove as much dead tissue as he could. He applied a layer of metronidazole cream to the wound cavity, then covered it with a nonadherent dressing. He then covered the wound with gauze, sealed the edges with medical adhesive tape, and applied a few drops of oil of wintergreen to the surface. A pan of charcoal briquettes was put under the bed, and a candle with Mrs. A.’s favorite scent was lit by the bedside. The physician then instructed Mrs. A.’s husband to repeat the procedure once daily for 1 week.

After 2 weeks, Mrs. A. and her husband said the foul odor had greatly decreased. She appeared more cheerful and energetic, especially after her grandchildren visited a few days earlier. The physician then instructed the husband to stop using metronidazole cream and to apply a hydrocolloid dressing every 3 days instead. He advised them to continue the rest of the process of applying a few drops of oil of wintergreen on the dressing surface, placing a pan of charcoal briquettes under the bed, and lighting a scented candle by the bedside.

FINISH THE RACE!

Complex nonhealing wounds are encountered across various healthcare settings. Wound malodor is an important component of nonhealing wounds, which adversely affects patients, families, and healthcare providers. Infection, slough, and exudate are the major causes of wound malodor. The essential steps to reduce malodor are to remove necrotic tissue, use antibacterial and odor-absorbing agents, apply appropriate odor “concealers,” educate families, and formulate a patient- and family-centered strategy (Table 1).
 

Acknowledgment: The authors would like to thank Sue Reif, CNP, for her assistance in completing the manuscript.

Wounds that fail to heal become more than mere skin lesions. Pain, malodor, and the accompanying psychological distress often complicate nonhealing wounds and impair quality of life.¹ Management of malodor requires perseverance, sensitivity, and familiarity with tools and procedures that range from surgical debridement to medical-grade honey.

Chronic, nonhealing wounds are defined as persisting for more than 6 months.² These lesions are incapable of undergoing anatomic and functional repair on their own. Commonly encountered nonhealing wounds include pressure ulcers, venous stasis ulcers, arterial insufficiency ulcers, and malignant cutaneous wounds.

Typically, the patient with a nonhealing wound is frail, debilitated, medically complex, and often faced with one or more life-limiting illnesses. Complete wound healing may therefore be unrealistic, and optimal wound management becomes the goal of care.^3,4

Healthcare providers encounter nonhealing wounds in varied settings—acute inpatient, outpatient, long-term, and home care. For instance, in the home care setting, a study of 383 patients enrolled in hospice found that 35% had skin ulcers and wounds.³ Half of those affected had pressure ulcers, 20% had ischemic ulcers, and 30% had other skin disorders such as stasis ulcers, burns, skin tears, and tumors. A larger study, also in hospice patients, found that 26% had pressure ulcers and 10% more developed them within 6 months.⁵

While pressure ulcers are the most common nonhealing wounds, malignant or fungating wounds are found in 5% to 10% of patients with metastatic disease, usually with cancers of the breast, head, and neck.⁶

The three major causes of wound malodor are slough, infection, and exudate

Maximizing wound care provides comfort, relieves suffering, and promotes quality of life.^3,7 To achieve these goals, clinicians must be familiar with strategies to manage complications associated with nonhealing wounds such as pain, malodor, and psychosocial adverse effects. Of these complications, malodor has been pointed out by both patients and caregivers as the most distressing.⁸

This article focuses on wound malodor, discusses the processes that cause wounds to emit an offensive smell, and outlines a comprehensive management approach.

MRS. A., AGE 61, WITH STAGE IV BREAST CANCER

Mrs. A., 61 years old, had a fungating mass in her left breast, which began as a small nodule and progressively enlarged to deform her breast over several months. Her oncologist subsequently staged the extent of her cancer as stage IV after workup revealed lung metastasis. Mrs. A. and her family decided to forgo cancer treatment, including radiotherapy, and to transition to hospice care after discussions with the oncologist.

Mrs. A. lived at home with her husband. Her daughter and three grandchildren all lived nearby.

When her hospice physician arrived at her home to meet her, a strong, pungent, and nauseating smell greeted him as he entered her bedroom. The patient said that for the past few months she had been increasingly distressed by the revolting odor. She rarely left home and had been ashamed to have people visit her, including her family.

On examination, the physician noticed a large fungating mass with yellowish discharge and necrotic tissue in her left breast. In addition to mild pain, she was immensely bothered by the strong odor coming from her breast.

THE IMPACT OF MALODOR

As seen in the case of Mrs. A., malodor has grave effects, both physical and psychological. Patients experience impaired or socially unacceptable body image, social rejection, personal shame, and embarrassment.^9,10 Feelings of fear, anxiety, and depression are common. If left uncontrolled, malodor results in social isolation, reluctance to engage in social activities, diminished appetite, and nausea. In addition, malodor is a constant reminder of patients’ pain and cancer, and it results in further suffering.¹¹

Reactions of family members and caregivers can worsen the situation.^9,12 Expressions of revulsion limit contact and inhibit intimacy, especially near the end of life. Caregivers are often frustrated and distressed over their inability to control the malodor. The environment becomes uninhabitable, and the malodor can permeate clothing, furniture, and living quarters.

Managing malodor can be emotionally draining, physically daunting, and frustrating for healthcare professionals, as several methods are usually employed, often in a trial-and-error approach, to achieve an acceptable degree of odor control. In addition, clinicians must face the challenge of treating malodorous wounds at very close distance without reacting in a way that offends or alarms patients and family members.¹³

MALODOR PRODUCTION: WHERE IS THAT SMELL COMING FROM?

All wounds can produce an odor.¹⁴ Wounds that are expected to heal typically emit a faint but not unpleasant odor, akin to fresh blood. Wounds colonized by Pseudomonas aeruginosa produce a fruity or grapelike odor that is tolerable. Malodor occurs with wounds infected by other gram-negative organisms or anaerobic bacteria.¹⁵ Similarly, wounds covered by necrotic tissue smell like decaying flesh.

Three major causes

The three major causes of wound malodor are slough, infection, and exudate (Figure 1).

Slough is dead or necrotic tissue, usually resulting from vascular compromise. Arterial ulcers, pressure ulcers, and malignant wounds all form slough from capillary occlusion, subsequent ischemia, and tissue necrosis.

Infection. Devitalized tissue, an ideal medium in which bacteria thrive, becomes the source of infection. Anaerobic bacteria are usually implicated in malodor. These include Bacteroides fragilis, Bacteroides prevotella, Clostridium perfringens, and Fusobacterium nucleatum.^16,17 Anaerobic organisms produce putrescine and cadaverine, which are largely responsible for the offensive odor.^16,18 Volatile fatty acids such as propionic, butyric, isovaleric, and valeric acid are formed from lipid catabolism by anaerobes and add to malodor.¹⁷ Aerobic bacteria such as Proteus, Klebsiella, and Pseudomonas species supercolonize necrotic tissue as well and contribute to malodor.^17,18

Exudate. Since nonhealing wounds undergo repeated cycles of inflammation, infection, and necrosis, accumulation of exudate becomes inevitable. Exudate typically is a pus-like fluid containing serum, fibrin, and white blood cells, which leak from blood vessels. In addition, bacteria that colonize chronic wounds filled with necrotic tissue activate proteases that degrade and liquefy dead tissue, thereby forming extensive amounts of exudate.¹⁹

Apart from slough, infection, and exudate, poor general hygiene and dressings left on for too long may contribute to malodor.¹⁶ Moisture-retentive dressings such as hydrocolloids leave an odor after removal. Dressings that liquefy upon contact with the wound surface leave a pus-like, potentially malodorous material.

MALODOR ASSESSMENT: DO YOU SMELL SOMETHING?

Various ways to document wound malodor can prove useful in guiding assessment and treatment. Descriptions such as “foul,” “putrid,” “fishy,” or “filled the room” vividly portray the initial presentation. A 10-point numerical scale similar to a numerical pain scale or a visual analogue scale can be used as a subjective measure.

Other grading methods, which to the authors’ knowledge are not validated, may be helpful. In a study that focused on patients suffering from malodorous gynecologic malignancies, von Gruenigen et al²⁰ used a 0-to-3 scale:

• 0 Absent
• 1 Not offensive
• 2 Offensive but tolerable
• 3 Offensive and intolerable.

A scale often adapted by other authors was devised by Baker and Haig,²¹ which clearly defines four classes:

• 1 Strong—odor is evident upon entering the room (6 to 10 feet from the patient) with the dressing intact
• 2 Moderate—odor is evident upon entering the room with dressing removed
• 3 Slight—odor is evident at close proximity to the patient when the dressing is removed
• 4 No odor—no odor is evident, even at the patient’s bedside with the dressing removed.

COMPREHENSIVE MANAGEMENT: HOW DO WE WIN THE ‘RACE’?

The acronym RACE outlines an approach to dealing with malodor. It stands for removal of necrotic tissue; antibacterials; odor concealers; and education and support (Table 1).

Remove necrotic tissue

An important step in eliminating malodor is to remove necrotic tissue. This starts with debridement, which decreases the incidence of infection and hastens wound closure.^22,23 Table 2 compares the different types of debridement.

Sharp or surgical debridement involves the use of a scalpel or scissors. This type of debridement may increase the risk of bleeding, pain, and malignant cell seeding in fungating wounds.^4,24

Enzymatic debridement employs chemicals with proteolytic action (eg, collagenase) to digest extracellular proteins in wounds.^18,25

Mechanical debridement involves aggressive therapies such as forceful irrigation and hydrotherapy, which may fail to discriminate between necrotic and viable tissues.^18,26

Biological debridement using maggots, which ingest bacteria and devitalized tissue, may cause increased wound bleeding and may be unacceptable for patients and families.^24,27

Autolytic debridement is often recommended, particularly if complete healing is not the primary goal.^17,24,28,29 Autolysis uses proteolytic enzymes and phagocytic cells present in the wound bed and wound fluid to clear devitalized tissue. It is easy, inexpensive, noninvasive, and painless,⁴ and it requires less frequent dressing changes relative to standard dressing or wet-to-dry dressing.

Autolytic debridement is commonly accomplished using hydrocolloid and hydrogel dressings.^15,29 Hydrocolloids are adhesive, occlusive, and conformable dressings that are suitable for wounds with low to moderate amounts of exudate. Upon contact with the wound surface, the dressing absorbs the exudate, forms a gel layer, and maintains a moist environment. Hydrocolloids are not recommended for infected wounds or for those with copious exudate as they may lead to maceration around the wound. A disadvantage of hydrocolloid dressings is their tendency to generate brown, often malodorous exudate when removed.

On the other hand, hydrogels in amorphous gel, dressing, sheet, or impregnated gauze form are water-based products that create a moist environment similar to hydrocolloids. Aside from causing minimal trauma to the wound bed when removed, the dressing’s cooling effect may bring some pain relief. Hydrogels are appropriate for dry wounds and for those with minimal exudate.

After debridement, the wound is cleansed and irrigated. A number of cleansers and solutions are available, but normal saline is a cheap alternative. To irrigate, experts recommend an 18- or 20-gauge intravenous catheter attached to a 30- or 60-mL syringe.¹⁵ This technique provides 8 to 15 psi of pressure, enough to cleanse the wound without causing tissue trauma.

Antibacterials and absorption

Antibacterials. Topical antibiotics have several advantages over systemic antibiotics in treating chronic wounds.^30,31 These include a high and sustained concentration of the antimicrobial at the site of infection, limited potential for systemic absorption and toxicity, reduced potential for antibiotic resistance, and drawing of the patient’s and caregiver’s attention to the wound.

Metronidazole is the most widely used topical antibacterial for malodor management. Its efficacy is likely due to the predominant involvement of anaerobic bacteria in foul-smelling wounds. Topical metronidazole is available as a gel and as a cream. A systematic review showed that on average, topical metronidazole was used once daily for 14 consecutive days.¹⁹ The layer of topical metronidazole is typically covered with a nonadherent primary dressing followed by an absorbent secondary dressing.

The best clinical evidence for topical metronidazole consists of case reports and series.^32–35 The largest of these studies was done by Finlay et al, who treated 47 patients with malodorous benign and malignant cutaneous wounds with 0.75% metronidazole gel daily.³² Forty-five (96%) of the patients reported significantly decreased odor by 14 days, as well as decreased pain, discharge, and surrounding cellulitis.

A randomized, placebo-controlled trial conducted by Bale et al had equivocal findings.⁹ All 41 patients who received metronidazole gel reported a decrease in malodor within 3 days of starting it. However, 76% of patients who received placebo also reported malodor control; in the final analysis, no significant difference was noted in the success rate between the two groups.

Metronidazole tablets can be crushed and sprinkled over the wound. As with metronidazole gel or cream, the crushed tablets are applied daily and covered by a primary nonadherent dressing and an absorbent secondary dressing. This off-label use of metronidazole serves as a cheaper alternative to commercially available topical preparations. To our knowledge, there has been no head-to-head trial comparing the two topical strategies.

Systemic metronidazole, often given orally, has been recommended if evidence of deep tissue or systemic infection is noted¹⁵ and in cases of fungating wounds with fistulas invading either the gastrointestinal or genitourinary tracts.¹⁸ Side effects such as nausea, neuropathy, and alcohol intolerance (ie, disulfiram reaction) may occur, which are not seen with topical metronidazole.

Both topical and systemic metronidazole can be used together on a time-limited basis for extensive malodorous wounds, such as fungating malignant wounds or stage IV sacral pressure ulcers.

Other antimicrobial agents used to treat malodor include silver-containing products, iodine-containing topical agents, mupirocin, bacitracin, neomycin, and polymyxin B.

Honey has been used for wound care since the era of the ancient Egyptians

Honey was used for wound care by the ancient Egyptians, and it is still used.³⁶ Its beneficial effects include antimicrobial, debriding, deodorizing, anti-inflammatory, and granulation tissue-stimulating. Honey has even been shown to significantly decrease skin colonization with various kinds of bacteria, including methicillin-resistant Staphylococcus aureus.³⁷ Medical-grade honey is preferred over table honey, as the latter is nonsterile and can contain Clostridium spores, which contaminate the wound.³⁸

Yogurt and buttermilk lower the pH of the wound and control bacterial proliferation to control malodor.^39,40 Either is applied for 10 to 15 minutes after the wound is cleansed and is then washed off thoroughly.

Absorbent dressings are used either over a layer of topical metronidazole and a nonadherent primary dressing or as a primary dressing itself. An absorbent dressing containing activated charcoal is used for rapid improvement, although cost may be prohibitive, especially in developing countries.^13,19 Another type of absorbent dressing, composed of polyester impregnated with sodium chloride, has been found to be useful in malodor control.⁴¹ An important pointer is to maintain a tight seal around the absorbent dressing to prevent leakage of exudate.

Concealers

Aromatics used to conceal malodor include scented candles, incense, fragrant flowers and plants, and air-freshener sprays. When circumstances allow, candles are good options since they conceal malodor by emitting fragrance, and the flame burns off foul-smelling chemicals. Aromatics such as coffee beans, vanilla beans, and cider vinegar can be placed in a pan and left under the patient’s bed or close to it. Drops of peppermint oil or oil of wintergreen can be placed on wound dressings.

Other odor concealers are adsorbent materials that attract and cause ions and molecules to adhere to their surface. Examples are charcoal, baking soda, and cat litter. As with other aromatics, these materials are placed in pans and left under the bed or near the patient.

Aromatics can have disadvantages, as certain scents, especially strong ones, can be nauseating for patients. Some fragrances trigger asthma or skin irritation. Patients and caregivers can be left with an unpleasant association of certain fragrances with malodor by conditioning.^15,17,18

Education and support

Concerns of the patient and family members need to be heard, addressed promptly, and reassessed with each visit, since uncontrolled malodor can be a chief source of caregiver fatigue.

Foremost in formulating a patient- and family-centered malodor management strategy is to commit to controlling malodor as much as possible. Regular follow-up appointments should be made, whether in the office or at home, to check on the patient’s progress and address new and ongoing concerns. Symptoms accompanying malodor, such as pain, bleeding, and sleep disturbance, need to be addressed, as they all affect quality of life.¹ Audience-appropriate educational materials should be made available.²⁶ Online resources that patients and families can explore include the websites of the Wound Ostomy and Continence Nurses Society (www.wocn.org) and the Association for the Advancement of Wound Care (aawconline.org).

Avoid expressing distress at odors in front of or within hearing of patients and families

Healthcare professionals need to be prepared to deal with problems and complications involving patients and family members that may arise in the course of treatment.¹² Problems include the cost and local unavailability of dressing supplies, insurance coverage for dressings and topical agents, lack of assistance at home, and fear of changing dressings. A cardinal rule for healthcare providers is to avoid expressing distress at odors in front of or within hearing of patients and families.

OTHER STRATEGIES: WHAT ELSE CAN WE DO?

Curcumin, the main biologically active compound in the herb turmeric, applied directly to wounds three times daily as an ointment, has been shown to have odor-controlling properties.⁴²

Sugar paste has been reported to control malodor by drawing out exudative and tissue fluid osmotically, and inhibiting bacterial growth.^16,17 Water is mixed with sugar (ie, granulated, caster, or powdered) to form a paste, with additives like glycerin and polyethylene glycol used to alter the consistency. Thick clay-like paste is good for wounds with large cavities, while thin paste is useful for wounds with small or superficial openings. The paste is applied twice daily and is covered by an absorbent dressing.

Pressure relief is vital in managing pressure ulcers.^18,43 Repositioning every 2 hours and using special devices, such as mattress overlays, alternating pressure mattresses, and low air loss mattresses, are frequently employed techniques.

If circumstances permit and when congruent with the patient’s goals of care, intra-arterial chemotherapy and radiotherapy can be contemplated for malignant fungating wounds.^44,45

Other strategies include opening the windows during dressing changes, increasing the frequency of dressing changes, promptly removing used dressings from the house, and ensuring good general hygiene.

CASE RESOLUTION

After telling her that he was committed to control the malodor or, if possible, eliminate it, Mrs. A.’s doctor prepared two lists of materials—one for himself and one for Mrs. A.’s husband. He returned the next day, brought out his supplies, asked Mrs. A. to lie in bed, and invited her husband to assist him.

He cleansed and irrigated the breast lesion with normal saline, making sure to remove as much dead tissue as he could. He applied a layer of metronidazole cream to the wound cavity, then covered it with a nonadherent dressing. He then covered the wound with gauze, sealed the edges with medical adhesive tape, and applied a few drops of oil of wintergreen to the surface. A pan of charcoal briquettes was put under the bed, and a candle with Mrs. A.’s favorite scent was lit by the bedside. The physician then instructed Mrs. A.’s husband to repeat the procedure once daily for 1 week.

After 2 weeks, Mrs. A. and her husband said the foul odor had greatly decreased. She appeared more cheerful and energetic, especially after her grandchildren visited a few days earlier. The physician then instructed the husband to stop using metronidazole cream and to apply a hydrocolloid dressing every 3 days instead. He advised them to continue the rest of the process of applying a few drops of oil of wintergreen on the dressing surface, placing a pan of charcoal briquettes under the bed, and lighting a scented candle by the bedside.

FINISH THE RACE!

Complex nonhealing wounds are encountered across various healthcare settings. Wound malodor is an important component of nonhealing wounds, which adversely affects patients, families, and healthcare providers. Infection, slough, and exudate are the major causes of wound malodor. The essential steps to reduce malodor are to remove necrotic tissue, use antibacterial and odor-absorbing agents, apply appropriate odor “concealers,” educate families, and formulate a patient- and family-centered strategy (Table 1).
 

Acknowledgment: The authors would like to thank Sue Reif, CNP, for her assistance in completing the manuscript.

Most people assume that electronic cigarettes (e-cigarettes) are safer than conventional tobacco products. Nevertheless, we should not encourage addicted smokers to try “vaping” as an alternative to nicotine replacement therapy, and we should discourage never-smokers from taking up vaping as vigorously as we try to discourage them from taking up smoking.

This article examines the prevailing assumptions and the evidence regarding the safety of e-cigarettes and traditional nicotine replacement therapy.

SMOKING IS DECLINING BUT FAR FROM GONE

While smoking rates have been declining over the past 50 years, the burden of disease attributable to tobacco use remains high. In the United States, it is estimated that nearly 6 million of those currently under the age of 18 will die of tobacco-related illnesses.¹ In the 50 years since the US surgeon general first reported on the health concerns related to tobacco, smoking has claimed the lives of nearly 21 million Americans¹ and continues to kill more than 400,000 every year.²

Even though the risks of smoking are well known, smoking remains one of the most difficult habits to quit. Indeed, about half of all smokers attempt to quit each year, but very few succeed.³

NICOTINE REPLACEMENT: GUM, PATCHES…E-CIGARETTES?

Smoking continues to kill more than 400,000 Americans every year

Nicotine replacement therapy was born out of the thought that, though nicotine is responsible for tobacco’s addictive quality, most tobacco-related disease is attributable to the 7,000 other substances found in tobacco smoke.⁴ Nicotine polacrilex gum was approved by the US Food and Drug Administration (FDA) in 1984, and nicotine transdermal film was approved in 1991.⁵

Nicotine replacement therapy, in the form of patches and gum, has been shown to improve the odds of successfully quitting smoking by a factor of nearly 1.5 to 2.⁶ Nicotine patches and gum were initially prescription medications but became available over the counter in 1996.⁷ They quickly became first-line agents for smoking cessation, and their over-the-counter availability softened any potential concerns about the possible deleterious health consequences of nicotine itself.

E-cigarettes—devices that generate a nicotine vapor that can be inhaled in a fashion that mimics the experience of smoking—were introduced in China in 2004.⁸ By 2012, sales of these devices in the United States had reached $500 million and in 2013 were expected to top $1 billion.^9,10

E-cigarette manufacturers make no therapeutic claims about their products, thus allowing them to escape regulation by the FDA as nicotine replacement therapy. A recent FDA proposal, however, is likely to change their “protected” status.¹¹ Despite the lack of regulation up to this point, patients generally assume that e-cigarettes are just another form of nicotine replacement therapy, even though they contain substances other than nicotine.

WHAT’S IN E-CIGARETTES?

Nicotine, which is bad in itself

E-cigarettes contain nicotine in varying amounts (some cartridges contain none at all). Though nicotine replacement therapy is less harmful than tobacco, nicotine by itself is associated with its own health problems, notably cancer, cardiovascular disease, birth defects (possibly), and poisoning.

Carcinogenesis. Nicotine plays a direct role in carcinogenesis through a variety of mechanisms, including increasing the activity of tumor growth-promoting transcription factors, decreasing apoptosis, and increasing angiogenesis in tumors.¹² Additionally, specific types of nicotinic acetylcholine receptors— eg, alpha 7 receptors, which are stimulated by nicotine—are found in many malignant tumors and are thought to play a role in tumor progression.¹² Blockade of alpha 7 nicotinic acetylcholine receptors has been shown to decrease the growth of certain cancers.¹²

However, these findings were from in vitro studies, and the concerns they raised have not been reflected in in vivo studies. Despite having been on the market for 30 years, nicotine replacement therapy has as yet not been associated with any “real world” increase in cancer risk.

Smoking is one of the leading risk factors for cervical cancer, and nicotine itself may play a contributing role. Nicotine has been shown to increase cellular proliferation in cervical cancer.¹³ Some evidence suggests that it may also play a role in the lymphogenic metastasis of cervical cancer.¹³

Cardiovascular disease. Nicotine has been linked to cardiovascular disease. It directly affects the heart’s rate and rhythm via nicotinic acetylcholine receptors in the peripheral autonomic nervous system. It impairs endothelial-dependent dilation of blood vessels in response to nitric oxide, and this inhibition in the coronary arteries may contribute to smoking-related heart disease.^14,15 Nicotine has also been shown to raise serum cholesterol levels, increase clot formation, and contribute to plaque formation by increasing vascular smooth muscle.¹⁴

Possible teratogenic effect. There is some theoretical concern regarding exposure to nicotine in utero, as nicotinic acetylcholine receptors develop before neurons, and nicotine may therefore interfere with the natural influence of acetylcholine on the development of this system.¹⁴

Consuming one vial of e-cigarette fluid could be fatal

Direct toxicity. Nicotine is toxic at high levels. The overdose potential associated with nicotine is particularly worrisome with e-cigarettes, as the nicotine solution they use is typically supplied in 5-mL, 10-mL, or 20-mL vials that range in concentration from 8.5 to 22.2 mg of nicotine per mL.¹⁶ The fatal single dose range of nicotine has been reported at 30 to 60 mg in adults and 10 mg in children and can be achieved by oral, intravenous, or transdermal absorption,¹⁶ so one vial, if consumed orally, could be fatal.

The number of calls to US poison control centers regarding e-cigarettes has increased, closely paralleling their rise in popularity. In 2010, there were only 30 e-cigarette related calls to poison control centers; in 2011 the number increased to 269, and in 2012 it had reached 459 and included one fatality that was deemed a suicide.^17–19 Even though such toxic nicotine overdoses are rare, physicians should exercise caution and avoid recommending e-cigarettes to individuals with mental confusion, psychotic disorders, or suicidality, who might consume an entire vial.

Possible positive effects? Smoking is one of the worst things that people can do to their body, but the picture is complicated by a few possible positive effects. In the brain, although smoking increases the risk of Alzheimer disease, it is associated with a lower risk of Parkinson disease. In the bowel, it increases the risk of Crohn disease but may decrease the risk of ulcerative colitis. Gahring and Rogers²⁰ pointed out that neuronal nicotinic receptors are present in nonneuronal cells throughout the body and proposed that expression of these receptors may play a role in mediating the consequences of nicotine use, both good and bad. The lesson may be that nicotine is very active in the body, its effects are complicated and still incompletely understood, and therefore we should not encourage people to inhale nicotine products ad lib.

Additives

E-cigarettes typically contain propylene glycol, flavorings, and glycerine. One study that analyzed the additive contents of e-cigarettes found that propylene glycol accounted for 66% of the fluid, glycerine 24%, and flavorings less than 0.1%.²¹ Propylene glycol is the substance typically used in theater fog machines and is used to generate the vapor in e-cigarettes. Other substances such as tobacco-specific nitrosamines and diethylene glycol have also been found in e-cigarettes in small amounts.²²

Propylene glycol, ‘generally recognized as safe’

Propylene glycol has been used in theater fog machines for years—think Phantom of the Opera. It is also widely used as a solvent in many consumer products and pharmaceuticals. The FDA classified it as “generally recognized as safe” on the basis of one study conducted in rats and monkeys over 60 years ago.²³ As other authors have noted, however, a major manufacturer of propylene glycol recommends that exposure to propylene glycol mist be avoided.^24,25 Potential concern over propylene glycol mist was heightened when it was discovered that of all industries, the entertainment business ranked first in terms of work-related asthma symptoms and had the fifth-highest rate of wheezing.^26,27

Studies conducted over the last several decades have raised numerous health concerns about the safety of propylene glycol (Table 1).^26,28–36 The studies of propylene glycol fog are particularly important, as they most closely resemble the route of exposure in e-cigarette users.

Wieslander et al²⁸ exposed 27 volunteers to propylene glycol mist for 1 minute in an aircraft simulator under training conditions. Exposures were high, ranging from 176 to 851 mg/m³ (mean = 309 mg/m³). Four volunteers who developed a cough exhibited evidence of airway obstruction as indicated by a 5% decrease in forced expiratory volume in 1 second (FEV₁), while the rest did not exhibit any change in FEV₁.

Moline et al²⁹ conducted a non-peer-reviewed study for the Actors Equity Association and the League of American Theaters and Producers of 439 actors exposed to theater fog. They found statistically significant evidence of throat and vocal cord inflammation with prolonged peak exposure to glycols and recommended that actors not be exposed to glycol concentrations exceeding 40 mg/m³.

Varughese et al²⁶ conducted a study in 101 volunteers at 19 sites. The mean concentration of glycol-based fog was much lower than that in the studies by Wieslander et al²⁸ and Moline et al,²⁹ at 0.49 mg/m³ (the maximum was 3.22 mg/m³). The investigators concluded that glycol-based fog was associated with deleterious respiratory effects and that employees’ exposure should be limited.

The health issues related to propylene glycol are unique to e-cigarettes compared with nicotine replacement therapy. Unfortunately, the most applicable data available are from studies of persons exposed to theater fog, which involved periodic exposure and likely do not emulate the deep inhalation, multiple times daily, of propylene glycol by e-cigarette smokers. A 2014 review of the chemistry of contaminants in e-cigarettes³⁷ concluded that estimated levels of propylene glycol exposure in e-cigarette users come close to the threshold limit value set by the American Conference of Governmental Industrial Hygienists, and should merit concern.

These studies and real-life experience in the theater, while limited in scope, should give physicians pause and should cause increased awareness of the possibility of e-cigarette-induced pulmonary and upper airway complications. If such complications should occur, discontinuation of vaping should be advised.

Contaminants

The issue of adulterants is common to both e-cigarettes and nicotine replacement therapy. Several unlisted substances have been found in analyzed samples of e-cigarette fluid, including tobacco-specific nitrosamines (TSNAs), diethylene glycol (found in only one e-cigarette cartridge), cotinine, anabasine, myosmine, and beta-nicotyrine.²² The tobacco-specific nitrosamines N´-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N-nitrosoanabasine, and nitrosoanatabine have been found in five e-cigarette cartridge samples from two manufacturers in amounts similar to those found in nicotine replacement products.²²

Goniewicz et al³⁸ tested the vapor generated by 12 e-cigarette brands and found trace amounts of TSNAs. NNN was present in the vapor of eight of the samples in concentrations ranging from 0.8 to 4.3 ng per 150 puffs, and NNK in the vapor of nine of the samples in concentrations ranging from 1.1 to 28.3 ng per 150 puffs. Neither NNN nor NNK was found in blank samples nor with the Nicorette inhalator tested in the same study.³⁸

Because TNSAs can be formed from nicotine and its metabolites, there is also concern that cancer-causing nitrosamines may be formed from nicotine after it is absorbed into the body (ie, endogenously). While endogenous formation of NNK from nicotine has never been demonstrated, endogenous formation of NNN has been seen in some nicotine patch users.³⁹ The presence of these nitrosamines has raised concern that e-cigarettes and nicotine replacement therapy may have carcinogenic potential. The amounts of tobacco-specific nitrosamines found in e-cigarettes are also found in some nicotine replacement products.⁴⁰

Investigators have examined a possible connection between e-cigarettes and potentially carcinogenic carbonyl compounds, including formaldehyde, acetaldehyde, and acrolein. Formaldehyde (a known carcinogen) and acetaldehyde (a potential carcinogen) have been detected in e-cigarette cartridges and vapor.^38,41–43 Acrolein, a mucosal irritant, has been found in e-cigarette vapor.^38,43 Goniewicz et al³⁸ suggested that acrolein may be formed by the heating of the glycerin contained in the e-cigarette solution.

An extensive review of the studies of possible contaminant exposures (including polycylic aromatic hydrocarbons, TSNAs, volatile organic compounds, diethylene glycol, and inorganic compounds) with e-cigarette use according to occupational hygiene standards concluded that there was no cause for concern about increased health risk.³⁷ The study by Goniewicz et al also concluded that using e-cigarettes instead of traditional cigarettes may significantly reduce exposure to some tobacco-specific toxins.³⁸

E-CIGARETTES VS NICOTINE REPLACEMENT

Traditional nicotine replacement therapy products are regulated by the FDA and therefore standardized in terms of their contents. E-cigarettes, on the other hand, are unregulated vehicles for supplying nicotine, and may pose other health risks. One such risk is related to exposure to propylene glycol, which has never been studied under conditions (in terms of mode of delivery, frequency of dosing, and total duration of exposure) that approximate the exposure associated with e-cigarettes. Furthermore, the high concentration of nicotine in e-cigarette fluid poses a real risk of toxicity and potentially fatal overdose.

Nicotine replacement therapy and e-cigarettes both maintain addiction to nicotine

Nicotine replacement therapy and e-cigarettes both maintain addiction to nicotine if used in a harm-reduction strategy as a maintenance medication. Whether the ongoing nicotine addiction makes it more likely that individuals would switch back and forth between nicotine replacement and tobacco-based products is not clear. Also not known is whether e-cigarettes may serve as the “gateway drug” by which teens enter into nicotine addiction, but we believe that the potential exists, as these products are potentially more appealing in terms of the lack of pungent smell, the perception of safety, and the variety of flavors of e-cigarettes.

The efficacy of nicotine replacement therapy in improving smoking cessation has been reviewed extensively elsewhere³⁷ and is beyond the scope of this article. E-cigarettes may be appealing to many cigarette smokers because they deliver smokeless nicotine, and they more closely emulate the actual experience of smoking compared with traditional nicotine replacement therapy. Though some evidence suggests that e-cigarettes may be modestly effective in helping tobacco smokers quit nicotine, they are not FDA-approved for smoking cessation and are not marketed for that indication.⁴⁴ Medical practitioners should see them for what they are: a new nicotine product with a novel delivery system that is not approved as treatment. Because of the inherent risks involved with e-cigarettes, medical practitioners are best advised to remain neutral on the relative value of e-cigarettes and should continue to motivate patients to discontinue nicotine use altogether.

Most people assume that electronic cigarettes (e-cigarettes) are safer than conventional tobacco products. Nevertheless, we should not encourage addicted smokers to try “vaping” as an alternative to nicotine replacement therapy, and we should discourage never-smokers from taking up vaping as vigorously as we try to discourage them from taking up smoking.

This article examines the prevailing assumptions and the evidence regarding the safety of e-cigarettes and traditional nicotine replacement therapy.

SMOKING IS DECLINING BUT FAR FROM GONE

While smoking rates have been declining over the past 50 years, the burden of disease attributable to tobacco use remains high. In the United States, it is estimated that nearly 6 million of those currently under the age of 18 will die of tobacco-related illnesses.¹ In the 50 years since the US surgeon general first reported on the health concerns related to tobacco, smoking has claimed the lives of nearly 21 million Americans¹ and continues to kill more than 400,000 every year.²

Even though the risks of smoking are well known, smoking remains one of the most difficult habits to quit. Indeed, about half of all smokers attempt to quit each year, but very few succeed.³

NICOTINE REPLACEMENT: GUM, PATCHES…E-CIGARETTES?

Smoking continues to kill more than 400,000 Americans every year

Nicotine replacement therapy was born out of the thought that, though nicotine is responsible for tobacco’s addictive quality, most tobacco-related disease is attributable to the 7,000 other substances found in tobacco smoke.⁴ Nicotine polacrilex gum was approved by the US Food and Drug Administration (FDA) in 1984, and nicotine transdermal film was approved in 1991.⁵

Nicotine replacement therapy, in the form of patches and gum, has been shown to improve the odds of successfully quitting smoking by a factor of nearly 1.5 to 2.⁶ Nicotine patches and gum were initially prescription medications but became available over the counter in 1996.⁷ They quickly became first-line agents for smoking cessation, and their over-the-counter availability softened any potential concerns about the possible deleterious health consequences of nicotine itself.

E-cigarettes—devices that generate a nicotine vapor that can be inhaled in a fashion that mimics the experience of smoking—were introduced in China in 2004.⁸ By 2012, sales of these devices in the United States had reached $500 million and in 2013 were expected to top $1 billion.^9,10

E-cigarette manufacturers make no therapeutic claims about their products, thus allowing them to escape regulation by the FDA as nicotine replacement therapy. A recent FDA proposal, however, is likely to change their “protected” status.¹¹ Despite the lack of regulation up to this point, patients generally assume that e-cigarettes are just another form of nicotine replacement therapy, even though they contain substances other than nicotine.

WHAT’S IN E-CIGARETTES?

Nicotine, which is bad in itself

E-cigarettes contain nicotine in varying amounts (some cartridges contain none at all). Though nicotine replacement therapy is less harmful than tobacco, nicotine by itself is associated with its own health problems, notably cancer, cardiovascular disease, birth defects (possibly), and poisoning.

Carcinogenesis. Nicotine plays a direct role in carcinogenesis through a variety of mechanisms, including increasing the activity of tumor growth-promoting transcription factors, decreasing apoptosis, and increasing angiogenesis in tumors.¹² Additionally, specific types of nicotinic acetylcholine receptors— eg, alpha 7 receptors, which are stimulated by nicotine—are found in many malignant tumors and are thought to play a role in tumor progression.¹² Blockade of alpha 7 nicotinic acetylcholine receptors has been shown to decrease the growth of certain cancers.¹²

However, these findings were from in vitro studies, and the concerns they raised have not been reflected in in vivo studies. Despite having been on the market for 30 years, nicotine replacement therapy has as yet not been associated with any “real world” increase in cancer risk.

Smoking is one of the leading risk factors for cervical cancer, and nicotine itself may play a contributing role. Nicotine has been shown to increase cellular proliferation in cervical cancer.¹³ Some evidence suggests that it may also play a role in the lymphogenic metastasis of cervical cancer.¹³

Cardiovascular disease. Nicotine has been linked to cardiovascular disease. It directly affects the heart’s rate and rhythm via nicotinic acetylcholine receptors in the peripheral autonomic nervous system. It impairs endothelial-dependent dilation of blood vessels in response to nitric oxide, and this inhibition in the coronary arteries may contribute to smoking-related heart disease.^14,15 Nicotine has also been shown to raise serum cholesterol levels, increase clot formation, and contribute to plaque formation by increasing vascular smooth muscle.¹⁴

Possible teratogenic effect. There is some theoretical concern regarding exposure to nicotine in utero, as nicotinic acetylcholine receptors develop before neurons, and nicotine may therefore interfere with the natural influence of acetylcholine on the development of this system.¹⁴

Consuming one vial of e-cigarette fluid could be fatal

Direct toxicity. Nicotine is toxic at high levels. The overdose potential associated with nicotine is particularly worrisome with e-cigarettes, as the nicotine solution they use is typically supplied in 5-mL, 10-mL, or 20-mL vials that range in concentration from 8.5 to 22.2 mg of nicotine per mL.¹⁶ The fatal single dose range of nicotine has been reported at 30 to 60 mg in adults and 10 mg in children and can be achieved by oral, intravenous, or transdermal absorption,¹⁶ so one vial, if consumed orally, could be fatal.

The number of calls to US poison control centers regarding e-cigarettes has increased, closely paralleling their rise in popularity. In 2010, there were only 30 e-cigarette related calls to poison control centers; in 2011 the number increased to 269, and in 2012 it had reached 459 and included one fatality that was deemed a suicide.^17–19 Even though such toxic nicotine overdoses are rare, physicians should exercise caution and avoid recommending e-cigarettes to individuals with mental confusion, psychotic disorders, or suicidality, who might consume an entire vial.

Possible positive effects? Smoking is one of the worst things that people can do to their body, but the picture is complicated by a few possible positive effects. In the brain, although smoking increases the risk of Alzheimer disease, it is associated with a lower risk of Parkinson disease. In the bowel, it increases the risk of Crohn disease but may decrease the risk of ulcerative colitis. Gahring and Rogers²⁰ pointed out that neuronal nicotinic receptors are present in nonneuronal cells throughout the body and proposed that expression of these receptors may play a role in mediating the consequences of nicotine use, both good and bad. The lesson may be that nicotine is very active in the body, its effects are complicated and still incompletely understood, and therefore we should not encourage people to inhale nicotine products ad lib.

Additives

E-cigarettes typically contain propylene glycol, flavorings, and glycerine. One study that analyzed the additive contents of e-cigarettes found that propylene glycol accounted for 66% of the fluid, glycerine 24%, and flavorings less than 0.1%.²¹ Propylene glycol is the substance typically used in theater fog machines and is used to generate the vapor in e-cigarettes. Other substances such as tobacco-specific nitrosamines and diethylene glycol have also been found in e-cigarettes in small amounts.²²

Propylene glycol, ‘generally recognized as safe’

Propylene glycol has been used in theater fog machines for years—think Phantom of the Opera. It is also widely used as a solvent in many consumer products and pharmaceuticals. The FDA classified it as “generally recognized as safe” on the basis of one study conducted in rats and monkeys over 60 years ago.²³ As other authors have noted, however, a major manufacturer of propylene glycol recommends that exposure to propylene glycol mist be avoided.^24,25 Potential concern over propylene glycol mist was heightened when it was discovered that of all industries, the entertainment business ranked first in terms of work-related asthma symptoms and had the fifth-highest rate of wheezing.^26,27

Studies conducted over the last several decades have raised numerous health concerns about the safety of propylene glycol (Table 1).^26,28–36 The studies of propylene glycol fog are particularly important, as they most closely resemble the route of exposure in e-cigarette users.

Wieslander et al²⁸ exposed 27 volunteers to propylene glycol mist for 1 minute in an aircraft simulator under training conditions. Exposures were high, ranging from 176 to 851 mg/m³ (mean = 309 mg/m³). Four volunteers who developed a cough exhibited evidence of airway obstruction as indicated by a 5% decrease in forced expiratory volume in 1 second (FEV₁), while the rest did not exhibit any change in FEV₁.

Moline et al²⁹ conducted a non-peer-reviewed study for the Actors Equity Association and the League of American Theaters and Producers of 439 actors exposed to theater fog. They found statistically significant evidence of throat and vocal cord inflammation with prolonged peak exposure to glycols and recommended that actors not be exposed to glycol concentrations exceeding 40 mg/m³.

Varughese et al²⁶ conducted a study in 101 volunteers at 19 sites. The mean concentration of glycol-based fog was much lower than that in the studies by Wieslander et al²⁸ and Moline et al,²⁹ at 0.49 mg/m³ (the maximum was 3.22 mg/m³). The investigators concluded that glycol-based fog was associated with deleterious respiratory effects and that employees’ exposure should be limited.

The health issues related to propylene glycol are unique to e-cigarettes compared with nicotine replacement therapy. Unfortunately, the most applicable data available are from studies of persons exposed to theater fog, which involved periodic exposure and likely do not emulate the deep inhalation, multiple times daily, of propylene glycol by e-cigarette smokers. A 2014 review of the chemistry of contaminants in e-cigarettes³⁷ concluded that estimated levels of propylene glycol exposure in e-cigarette users come close to the threshold limit value set by the American Conference of Governmental Industrial Hygienists, and should merit concern.

These studies and real-life experience in the theater, while limited in scope, should give physicians pause and should cause increased awareness of the possibility of e-cigarette-induced pulmonary and upper airway complications. If such complications should occur, discontinuation of vaping should be advised.

Contaminants

The issue of adulterants is common to both e-cigarettes and nicotine replacement therapy. Several unlisted substances have been found in analyzed samples of e-cigarette fluid, including tobacco-specific nitrosamines (TSNAs), diethylene glycol (found in only one e-cigarette cartridge), cotinine, anabasine, myosmine, and beta-nicotyrine.²² The tobacco-specific nitrosamines N´-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N-nitrosoanabasine, and nitrosoanatabine have been found in five e-cigarette cartridge samples from two manufacturers in amounts similar to those found in nicotine replacement products.²²

Goniewicz et al³⁸ tested the vapor generated by 12 e-cigarette brands and found trace amounts of TSNAs. NNN was present in the vapor of eight of the samples in concentrations ranging from 0.8 to 4.3 ng per 150 puffs, and NNK in the vapor of nine of the samples in concentrations ranging from 1.1 to 28.3 ng per 150 puffs. Neither NNN nor NNK was found in blank samples nor with the Nicorette inhalator tested in the same study.³⁸

Because TNSAs can be formed from nicotine and its metabolites, there is also concern that cancer-causing nitrosamines may be formed from nicotine after it is absorbed into the body (ie, endogenously). While endogenous formation of NNK from nicotine has never been demonstrated, endogenous formation of NNN has been seen in some nicotine patch users.³⁹ The presence of these nitrosamines has raised concern that e-cigarettes and nicotine replacement therapy may have carcinogenic potential. The amounts of tobacco-specific nitrosamines found in e-cigarettes are also found in some nicotine replacement products.⁴⁰

Investigators have examined a possible connection between e-cigarettes and potentially carcinogenic carbonyl compounds, including formaldehyde, acetaldehyde, and acrolein. Formaldehyde (a known carcinogen) and acetaldehyde (a potential carcinogen) have been detected in e-cigarette cartridges and vapor.^38,41–43 Acrolein, a mucosal irritant, has been found in e-cigarette vapor.^38,43 Goniewicz et al³⁸ suggested that acrolein may be formed by the heating of the glycerin contained in the e-cigarette solution.

An extensive review of the studies of possible contaminant exposures (including polycylic aromatic hydrocarbons, TSNAs, volatile organic compounds, diethylene glycol, and inorganic compounds) with e-cigarette use according to occupational hygiene standards concluded that there was no cause for concern about increased health risk.³⁷ The study by Goniewicz et al also concluded that using e-cigarettes instead of traditional cigarettes may significantly reduce exposure to some tobacco-specific toxins.³⁸

E-CIGARETTES VS NICOTINE REPLACEMENT

Traditional nicotine replacement therapy products are regulated by the FDA and therefore standardized in terms of their contents. E-cigarettes, on the other hand, are unregulated vehicles for supplying nicotine, and may pose other health risks. One such risk is related to exposure to propylene glycol, which has never been studied under conditions (in terms of mode of delivery, frequency of dosing, and total duration of exposure) that approximate the exposure associated with e-cigarettes. Furthermore, the high concentration of nicotine in e-cigarette fluid poses a real risk of toxicity and potentially fatal overdose.

Nicotine replacement therapy and e-cigarettes both maintain addiction to nicotine

Nicotine replacement therapy and e-cigarettes both maintain addiction to nicotine if used in a harm-reduction strategy as a maintenance medication. Whether the ongoing nicotine addiction makes it more likely that individuals would switch back and forth between nicotine replacement and tobacco-based products is not clear. Also not known is whether e-cigarettes may serve as the “gateway drug” by which teens enter into nicotine addiction, but we believe that the potential exists, as these products are potentially more appealing in terms of the lack of pungent smell, the perception of safety, and the variety of flavors of e-cigarettes.

The efficacy of nicotine replacement therapy in improving smoking cessation has been reviewed extensively elsewhere³⁷ and is beyond the scope of this article. E-cigarettes may be appealing to many cigarette smokers because they deliver smokeless nicotine, and they more closely emulate the actual experience of smoking compared with traditional nicotine replacement therapy. Though some evidence suggests that e-cigarettes may be modestly effective in helping tobacco smokers quit nicotine, they are not FDA-approved for smoking cessation and are not marketed for that indication.⁴⁴ Medical practitioners should see them for what they are: a new nicotine product with a novel delivery system that is not approved as treatment. Because of the inherent risks involved with e-cigarettes, medical practitioners are best advised to remain neutral on the relative value of e-cigarettes and should continue to motivate patients to discontinue nicotine use altogether.

Most people assume that electronic cigarettes (e-cigarettes) are safer than conventional tobacco products. Nevertheless, we should not encourage addicted smokers to try “vaping” as an alternative to nicotine replacement therapy, and we should discourage never-smokers from taking up vaping as vigorously as we try to discourage them from taking up smoking.

This article examines the prevailing assumptions and the evidence regarding the safety of e-cigarettes and traditional nicotine replacement therapy.

SMOKING IS DECLINING BUT FAR FROM GONE

While smoking rates have been declining over the past 50 years, the burden of disease attributable to tobacco use remains high. In the United States, it is estimated that nearly 6 million of those currently under the age of 18 will die of tobacco-related illnesses.¹ In the 50 years since the US surgeon general first reported on the health concerns related to tobacco, smoking has claimed the lives of nearly 21 million Americans¹ and continues to kill more than 400,000 every year.²

Even though the risks of smoking are well known, smoking remains one of the most difficult habits to quit. Indeed, about half of all smokers attempt to quit each year, but very few succeed.³

NICOTINE REPLACEMENT: GUM, PATCHES…E-CIGARETTES?

Smoking continues to kill more than 400,000 Americans every year

Nicotine replacement therapy was born out of the thought that, though nicotine is responsible for tobacco’s addictive quality, most tobacco-related disease is attributable to the 7,000 other substances found in tobacco smoke.⁴ Nicotine polacrilex gum was approved by the US Food and Drug Administration (FDA) in 1984, and nicotine transdermal film was approved in 1991.⁵

Nicotine replacement therapy, in the form of patches and gum, has been shown to improve the odds of successfully quitting smoking by a factor of nearly 1.5 to 2.⁶ Nicotine patches and gum were initially prescription medications but became available over the counter in 1996.⁷ They quickly became first-line agents for smoking cessation, and their over-the-counter availability softened any potential concerns about the possible deleterious health consequences of nicotine itself.

E-cigarettes—devices that generate a nicotine vapor that can be inhaled in a fashion that mimics the experience of smoking—were introduced in China in 2004.⁸ By 2012, sales of these devices in the United States had reached $500 million and in 2013 were expected to top $1 billion.^9,10

E-cigarette manufacturers make no therapeutic claims about their products, thus allowing them to escape regulation by the FDA as nicotine replacement therapy. A recent FDA proposal, however, is likely to change their “protected” status.¹¹ Despite the lack of regulation up to this point, patients generally assume that e-cigarettes are just another form of nicotine replacement therapy, even though they contain substances other than nicotine.

WHAT’S IN E-CIGARETTES?

Nicotine, which is bad in itself

E-cigarettes contain nicotine in varying amounts (some cartridges contain none at all). Though nicotine replacement therapy is less harmful than tobacco, nicotine by itself is associated with its own health problems, notably cancer, cardiovascular disease, birth defects (possibly), and poisoning.

Carcinogenesis. Nicotine plays a direct role in carcinogenesis through a variety of mechanisms, including increasing the activity of tumor growth-promoting transcription factors, decreasing apoptosis, and increasing angiogenesis in tumors.¹² Additionally, specific types of nicotinic acetylcholine receptors— eg, alpha 7 receptors, which are stimulated by nicotine—are found in many malignant tumors and are thought to play a role in tumor progression.¹² Blockade of alpha 7 nicotinic acetylcholine receptors has been shown to decrease the growth of certain cancers.¹²

However, these findings were from in vitro studies, and the concerns they raised have not been reflected in in vivo studies. Despite having been on the market for 30 years, nicotine replacement therapy has as yet not been associated with any “real world” increase in cancer risk.

Smoking is one of the leading risk factors for cervical cancer, and nicotine itself may play a contributing role. Nicotine has been shown to increase cellular proliferation in cervical cancer.¹³ Some evidence suggests that it may also play a role in the lymphogenic metastasis of cervical cancer.¹³

Cardiovascular disease. Nicotine has been linked to cardiovascular disease. It directly affects the heart’s rate and rhythm via nicotinic acetylcholine receptors in the peripheral autonomic nervous system. It impairs endothelial-dependent dilation of blood vessels in response to nitric oxide, and this inhibition in the coronary arteries may contribute to smoking-related heart disease.^14,15 Nicotine has also been shown to raise serum cholesterol levels, increase clot formation, and contribute to plaque formation by increasing vascular smooth muscle.¹⁴

Possible teratogenic effect. There is some theoretical concern regarding exposure to nicotine in utero, as nicotinic acetylcholine receptors develop before neurons, and nicotine may therefore interfere with the natural influence of acetylcholine on the development of this system.¹⁴

Consuming one vial of e-cigarette fluid could be fatal

Direct toxicity. Nicotine is toxic at high levels. The overdose potential associated with nicotine is particularly worrisome with e-cigarettes, as the nicotine solution they use is typically supplied in 5-mL, 10-mL, or 20-mL vials that range in concentration from 8.5 to 22.2 mg of nicotine per mL.¹⁶ The fatal single dose range of nicotine has been reported at 30 to 60 mg in adults and 10 mg in children and can be achieved by oral, intravenous, or transdermal absorption,¹⁶ so one vial, if consumed orally, could be fatal.

The number of calls to US poison control centers regarding e-cigarettes has increased, closely paralleling their rise in popularity. In 2010, there were only 30 e-cigarette related calls to poison control centers; in 2011 the number increased to 269, and in 2012 it had reached 459 and included one fatality that was deemed a suicide.^17–19 Even though such toxic nicotine overdoses are rare, physicians should exercise caution and avoid recommending e-cigarettes to individuals with mental confusion, psychotic disorders, or suicidality, who might consume an entire vial.

Possible positive effects? Smoking is one of the worst things that people can do to their body, but the picture is complicated by a few possible positive effects. In the brain, although smoking increases the risk of Alzheimer disease, it is associated with a lower risk of Parkinson disease. In the bowel, it increases the risk of Crohn disease but may decrease the risk of ulcerative colitis. Gahring and Rogers²⁰ pointed out that neuronal nicotinic receptors are present in nonneuronal cells throughout the body and proposed that expression of these receptors may play a role in mediating the consequences of nicotine use, both good and bad. The lesson may be that nicotine is very active in the body, its effects are complicated and still incompletely understood, and therefore we should not encourage people to inhale nicotine products ad lib.

Additives

E-cigarettes typically contain propylene glycol, flavorings, and glycerine. One study that analyzed the additive contents of e-cigarettes found that propylene glycol accounted for 66% of the fluid, glycerine 24%, and flavorings less than 0.1%.²¹ Propylene glycol is the substance typically used in theater fog machines and is used to generate the vapor in e-cigarettes. Other substances such as tobacco-specific nitrosamines and diethylene glycol have also been found in e-cigarettes in small amounts.²²

Propylene glycol, ‘generally recognized as safe’

Propylene glycol has been used in theater fog machines for years—think Phantom of the Opera. It is also widely used as a solvent in many consumer products and pharmaceuticals. The FDA classified it as “generally recognized as safe” on the basis of one study conducted in rats and monkeys over 60 years ago.²³ As other authors have noted, however, a major manufacturer of propylene glycol recommends that exposure to propylene glycol mist be avoided.^24,25 Potential concern over propylene glycol mist was heightened when it was discovered that of all industries, the entertainment business ranked first in terms of work-related asthma symptoms and had the fifth-highest rate of wheezing.^26,27

Studies conducted over the last several decades have raised numerous health concerns about the safety of propylene glycol (Table 1).^26,28–36 The studies of propylene glycol fog are particularly important, as they most closely resemble the route of exposure in e-cigarette users.

Wieslander et al²⁸ exposed 27 volunteers to propylene glycol mist for 1 minute in an aircraft simulator under training conditions. Exposures were high, ranging from 176 to 851 mg/m³ (mean = 309 mg/m³). Four volunteers who developed a cough exhibited evidence of airway obstruction as indicated by a 5% decrease in forced expiratory volume in 1 second (FEV₁), while the rest did not exhibit any change in FEV₁.

Moline et al²⁹ conducted a non-peer-reviewed study for the Actors Equity Association and the League of American Theaters and Producers of 439 actors exposed to theater fog. They found statistically significant evidence of throat and vocal cord inflammation with prolonged peak exposure to glycols and recommended that actors not be exposed to glycol concentrations exceeding 40 mg/m³.

Varughese et al²⁶ conducted a study in 101 volunteers at 19 sites. The mean concentration of glycol-based fog was much lower than that in the studies by Wieslander et al²⁸ and Moline et al,²⁹ at 0.49 mg/m³ (the maximum was 3.22 mg/m³). The investigators concluded that glycol-based fog was associated with deleterious respiratory effects and that employees’ exposure should be limited.

The health issues related to propylene glycol are unique to e-cigarettes compared with nicotine replacement therapy. Unfortunately, the most applicable data available are from studies of persons exposed to theater fog, which involved periodic exposure and likely do not emulate the deep inhalation, multiple times daily, of propylene glycol by e-cigarette smokers. A 2014 review of the chemistry of contaminants in e-cigarettes³⁷ concluded that estimated levels of propylene glycol exposure in e-cigarette users come close to the threshold limit value set by the American Conference of Governmental Industrial Hygienists, and should merit concern.

These studies and real-life experience in the theater, while limited in scope, should give physicians pause and should cause increased awareness of the possibility of e-cigarette-induced pulmonary and upper airway complications. If such complications should occur, discontinuation of vaping should be advised.

Contaminants

The issue of adulterants is common to both e-cigarettes and nicotine replacement therapy. Several unlisted substances have been found in analyzed samples of e-cigarette fluid, including tobacco-specific nitrosamines (TSNAs), diethylene glycol (found in only one e-cigarette cartridge), cotinine, anabasine, myosmine, and beta-nicotyrine.²² The tobacco-specific nitrosamines N´-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N-nitrosoanabasine, and nitrosoanatabine have been found in five e-cigarette cartridge samples from two manufacturers in amounts similar to those found in nicotine replacement products.²²

Goniewicz et al³⁸ tested the vapor generated by 12 e-cigarette brands and found trace amounts of TSNAs. NNN was present in the vapor of eight of the samples in concentrations ranging from 0.8 to 4.3 ng per 150 puffs, and NNK in the vapor of nine of the samples in concentrations ranging from 1.1 to 28.3 ng per 150 puffs. Neither NNN nor NNK was found in blank samples nor with the Nicorette inhalator tested in the same study.³⁸

Because TNSAs can be formed from nicotine and its metabolites, there is also concern that cancer-causing nitrosamines may be formed from nicotine after it is absorbed into the body (ie, endogenously). While endogenous formation of NNK from nicotine has never been demonstrated, endogenous formation of NNN has been seen in some nicotine patch users.³⁹ The presence of these nitrosamines has raised concern that e-cigarettes and nicotine replacement therapy may have carcinogenic potential. The amounts of tobacco-specific nitrosamines found in e-cigarettes are also found in some nicotine replacement products.⁴⁰

Investigators have examined a possible connection between e-cigarettes and potentially carcinogenic carbonyl compounds, including formaldehyde, acetaldehyde, and acrolein. Formaldehyde (a known carcinogen) and acetaldehyde (a potential carcinogen) have been detected in e-cigarette cartridges and vapor.^38,41–43 Acrolein, a mucosal irritant, has been found in e-cigarette vapor.^38,43 Goniewicz et al³⁸ suggested that acrolein may be formed by the heating of the glycerin contained in the e-cigarette solution.

An extensive review of the studies of possible contaminant exposures (including polycylic aromatic hydrocarbons, TSNAs, volatile organic compounds, diethylene glycol, and inorganic compounds) with e-cigarette use according to occupational hygiene standards concluded that there was no cause for concern about increased health risk.³⁷ The study by Goniewicz et al also concluded that using e-cigarettes instead of traditional cigarettes may significantly reduce exposure to some tobacco-specific toxins.³⁸

E-CIGARETTES VS NICOTINE REPLACEMENT

Traditional nicotine replacement therapy products are regulated by the FDA and therefore standardized in terms of their contents. E-cigarettes, on the other hand, are unregulated vehicles for supplying nicotine, and may pose other health risks. One such risk is related to exposure to propylene glycol, which has never been studied under conditions (in terms of mode of delivery, frequency of dosing, and total duration of exposure) that approximate the exposure associated with e-cigarettes. Furthermore, the high concentration of nicotine in e-cigarette fluid poses a real risk of toxicity and potentially fatal overdose.

Nicotine replacement therapy and e-cigarettes both maintain addiction to nicotine

Nicotine replacement therapy and e-cigarettes both maintain addiction to nicotine if used in a harm-reduction strategy as a maintenance medication. Whether the ongoing nicotine addiction makes it more likely that individuals would switch back and forth between nicotine replacement and tobacco-based products is not clear. Also not known is whether e-cigarettes may serve as the “gateway drug” by which teens enter into nicotine addiction, but we believe that the potential exists, as these products are potentially more appealing in terms of the lack of pungent smell, the perception of safety, and the variety of flavors of e-cigarettes.

The efficacy of nicotine replacement therapy in improving smoking cessation has been reviewed extensively elsewhere³⁷ and is beyond the scope of this article. E-cigarettes may be appealing to many cigarette smokers because they deliver smokeless nicotine, and they more closely emulate the actual experience of smoking compared with traditional nicotine replacement therapy. Though some evidence suggests that e-cigarettes may be modestly effective in helping tobacco smokers quit nicotine, they are not FDA-approved for smoking cessation and are not marketed for that indication.⁴⁴ Medical practitioners should see them for what they are: a new nicotine product with a novel delivery system that is not approved as treatment. Because of the inherent risks involved with e-cigarettes, medical practitioners are best advised to remain neutral on the relative value of e-cigarettes and should continue to motivate patients to discontinue nicotine use altogether.

Insulin therapy is one of the most effective tools clinicians can use to help patients reach their individualized hemoglobin A_1c target. However, decisions about when and how to start insulin therapy have to be individualized to the needs and goals of each patient. Many insulin options are available, one of the most common being the addition of basal insulin to oral antidiabetic drugs. Although patients are often reluctant to start insulin, this reluctance can be overcome through patient education and hands-on training.

Here, we review hemoglobin A_1c targets, factors that determine when to start insulin therapy, and the different regimens that can be used.

MOST PATIENTS EVENTUALLY NEED INSULIN

Type 2 diabetes mellitus is a chronic progressive disease associated with insulin resistance, beta-cell dysfunction, and decreased insulin secretion. Consequently, most patients eventually require insulin therapy to reduce the risk of long-term complications.

The efficacy of therapy can be assessed by measuring hemoglobin A_1c, an important marker of the chronic hyperglycemic state. The hemoglobin A_1c value can be reported as a ratio (%) standardized against the results of the Diabetes Control and Complications Trial,¹ or as International Federation of Clinical Chemistry units (mmol/mol).² Table 1 shows the relationship between hemoglobin A_1c and average glucose values.³

WHAT IS AN APPROPRIATE HEMOGLOBIN A_1c TARGET?

The short answer is, “It depends.”

Currently, the American Association of Clinical Endocrinologists (AACE) supports a hemoglobin A_1c goal of less than 6.5% for otherwise healthy patients but states that the goal should be individualized for patients with concurrent illnesses or at risk of hypoglycemia.⁴

On the other hand, the American Diabetes Association (ADA) recommends a higher hemoglobin A_1c target of less than 7% for most adults with type 2 diabetes mellitus.⁵ This value was shown to be associated with a reduction in the microvascular and macrovascular complications of diabetes.

Yet when three large trials^6–8 recently compared intensive and standard glucose control regimens, tighter glucose control failed to improve cardiovascular outcomes. Moreover, in one of the trials,⁷ patients receiving intensive treatment had a higher rate of all-cause mortality. Details:

• Action in Diabetes and Vascular Disease (ADVANCE): 11,140 patients; average hemoglobin A_1c levels 6.5% vs 7.3%⁶
• Action to Control Cardiovascular Risk in Diabetes (ACCORD): 10,251 patients; average hemoglobin A_1c levels 6.4% vs 7.5%⁷
• Veterans Affairs Diabetes Trial (VADT): 1,791 patients; average hemoglobin A_1c levels 6.9% vs 8.4%.⁸

Similarly, a 2013 Cochrane review⁹ that included 28 randomized controlled trials concluded that intensive control (in 18,717 patients) did not decrease all-cause and cardiovascular mortality rates compared with traditional glucose control (in 16,195 patients), and it increased the risk of hypoglycemia and serious adverse events.

The AACE and ADA are moving away from one-size-fits-all and toward individualized recommendations

As a result, the ADA⁵ states that a hemoglobin A_1c target less than 6.5% is optional for patients with a long life expectancy, short duration of diabetes, low risk of hypoglycemia, and no significant cardiovascular disease. The ADA further defines a hemoglobin A_1c goal of less than 8% for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, and long-standing diabetes.

Therefore, the AACE and ADA are moving away from “one-size-fits-all” goals and toward individualizing their recommendations.

WHEN SHOULD INSULIN BE STARTED?

Physicians should consider the needs and preferences of each patient and individualize the treatment. The most recent recommendations from the ADA⁵ stress the importance of a patient-centered approach, with multiple factors taken into account. These include the patient’s attitude, expected compliance with treatment, risk of hypoglycemia, disease duration, life expectancy, and comorbidities, and the side effects of oral medications and insulin.

Compared with previous guidelines, there are fewer rules on how and when to start insulin therapy. But absolute and relative indications for insulin therapy should be considered in patients with the following:

Absolute indications for insulin

• Ketoacidosis or catabolic symptoms, including ketonuria
• Newly diagnosed type 2 diabetes with pronounced hyperglycemia (glucose ≥ 300 mg/dL or hemoglobin A_1c ≥ 10.0%) with or without severe symptoms, including weight loss, polyuria, or polydipsia¹⁰
• Uncontrolled type 2 diabetes mellitus despite using one, two, or more oral antidiabetic drugs or glucagon-like peptide 1 (GLP-1) receptor agonists
• Gestational diabetes
• Preference for insulin.

Relative indications for insulin

• Hospitalized for surgery or acute illnesses
• Advanced renal or hepatic disease
• Inability to afford the cost or tolerate the side effects of oral antidiabetic drugs and GLP-1 receptor agonists.

Depending on the situation, blood glucose is measured fasting, before meals, or after meals after initiating or adjusting insulin regimens (Table 2).

WHAT ARE THE INSULIN REGIMENS?

Basal insulin

In the early stages of type 2 diabetes, metformin alone or in combination with another oral antidiabetic drug or with a GLP-1 receptor agonist is often used along with healthy eating, weight control, and increased physical activity.

When the target hemoglobin A_1c cannot be achieved with one or two noninsulin drugs, the ADA suggests basal insulin be added to metformin or a two-medication regimen that includes metformin (Table 3). However, recent evidence suggests that combining a GLP-1 receptor agonist with basal insulin, in a regimen without metformin, is safe and improves glycemic control without hypoglycemia or weight gain.¹¹

While a total daily dose of insulin of 0.1 to 0.2 units/kg could be initially used in patients with a hemoglobin A_1c level less than 8%, a higher dose of 0.2 to 0.3 units/kg is required if the hemoglobin A_1c level is between 8% and 10%. The dose can be titrated once or twice weekly if the fasting glucose is above the target level (usually < 130 mg/dL). If hypoglycemia develops (glucose < 70 mg/dL), the insulin dose should be reduced by 10% to 20%.¹⁰

Available basal insulins include glargine, detemir, and neutral protamine Hagedorn (NPH) (Table 4).^12–14 Because glargine and detemir offer better pharmacokinetic properties, less variability in response, and less risk of hypoglycemia, they are preferred over NPH. Glargine has a relatively constant plasma concentration over 24 hours, allowing once-daily dosing at any time during the day (Figure 1).¹⁵ The dose should be taken at the same time every day. Detemir and NPH are usually taken once or twice daily.

Adapted from Hirsch IB. Insulin analogues. N Engl J Med 2005; 352:174-183. Copyright 2005, Massachusetts Medical Society.

Patients treated once daily should take the dose with the evening meal or at bedtime. Patients who require a twice-daily regimen can take the first dose with breakfast and the second one with the evening meal, at bedtime, or 12 hours after the morning dose.

The randomized Treat-to-Target trial,¹⁶ in 756 patients, showed that both glargine and NPH, when added to oral therapy in patients with type 2 diabetes, achieve the target hemoglobin A_1c, but NPH is associated with more episodes of nocturnal hypoglycemia. Similar results were found when NPH was compared with detemir insulin.¹⁷

A Cochrane review¹⁸ suggested that glargine and detemir are similar in efficacy and safety. However, detemir often needs to be injected twice daily, in a higher dose, and is associated with less weight gain. Furthermore, a meta-analysis of 46 randomized clinical trials¹⁹ showed that the weight increase at 1 year is less in patients treated with basal than with twice-daily or prandial regimens.

The ADA suggests basal insulin be added to metformin alone or a regimen that includes metformin

A noninterventional longitudinal study²⁰ in 2,179 patients newly started on insulin showed that the mean weight increase at 1 year was 1.78 kg, and 24% of patients gained more than 5 kg. However, the factors independently associated with the weight gain were a higher hemoglobin A_1c at baseline, a higher insulin dose at baseline and at 1 year, and a lower baseline body mass index, but not the type of insulin regimen.

Currently, a new class of ultralong-acting basal insulins is being studied. Insulins in this class are approved in other countries, but the US Food and Drug Administration requires additional data for approval. Ultralong-acting insulins are expected to reduce the risk of hypoglycemia, specifically the risk of nocturnal episodes. Also, given their longer duration of action and stable steady-state pharmacokinetics, they will offer flexibility in the dose timing.²¹

Basal-bolus regimens

Basal insulin often does not control postprandial hyperglycemia. The need for multiple doses of insulin (including one or more preprandial doses) is suggested by postprandial glucose values above target (usually > 180 mg/dL) or by a hemoglobin A_1c above goal despite well-controlled fasting glucose levels. This usually becomes evident when the total daily dose of basal insulin exceeds 0.5 units/kg. Patients newly diagnosed with diabetes who have a hemoglobin A_1c higher than 10% may also respond better to an initial basal-bolus regimen.

Available bolus insulins include lispro, aspart, glulisine, regular insulin, and the newly approved Technosphere inhaled regular insulin (Table 4).^12–14 They can be taken before each meal, and the total bolus dose usually represents 50% of the total daily dose.²² Rapid-acting insulins have faster onset, shorter duration of action, and more predictable pharmacokinetics, which makes them preferable to regular insulin (Figure 1).¹⁵ Inhaled insulin is another option, but it is contraindicated in patients with chronic obstructive pulmonary disease or asthma because of the increased risk of acute bronchospasm.¹²

Alternatively, the transition to a basal-bolus regimen can be accomplished with a single dose of bolus insulin before the main meal, using a dose that represents approximately 10% of the total daily dose. Additional bolus doses can be added later based on the glycemic control. The adjustment of the preprandial insulin dose is done once or twice weekly, based on the postprandial glucose levels.¹⁰

Premixed combinations of long- and short-acting insulins in ratios of 50% to 50%, 70% to 30%, or 75% to 25% can be considered in patients who cannot adhere to a complex insulin regimen. A propensity-matched comparison of different insulin regimens (basal, premixed, mealtime plus basal, and mealtime) in patients with type 2 diabetes revealed that the hemoglobin A_1c reduction was similar between the different groups.²³ However, the number of hypoglycemic episodes was higher in the premixed insulin group, and the weight gain was less in the basal insulin group.

While premixed insulins require fewer injections, they do not provide dosing flexibility. In other words, dose adjustments for premixed insulins lead to increases in both basal and bolus amounts even though a dose adjustment is needed for only one insulin type. Thus, this is a common reason for increased hypoglycemic episodes.

Continuous subcutaneous insulin infusion

Patients who are engaged in their care are more likely to succeed in their treatment

A meta-analysis showed that continuous subcutaneous insulin infusion (ie, use of an insulin pump) was similar to intensive therapy with multiple daily insulin injections in terms of glycemic control and hypoglycemia.²⁴ Since both options can lead to similar glucose control, additional factors to consider when initiating insulin infusion include lifestyle and technical expertise. Some patients may or may not prefer having a pump attached for nearly all daily activities. Additionally, this type of therapy is complex and requires significant training to ensure efficacy and safety.²⁵

WHAT IS THE COST OF INSULIN THERAPY?

A final factor to keep in mind when initiating insulin is cost (Table 4).^12–14 Asking patients to check their prescription insurance formulary is important to ensure that an affordable option is selected. If patients do not have prescription insurance, medication assistance programs could be an option. However, if a patient is considering an insulin pump, insurance coverage is essential. Depending on the manufacturer, insulin pumps cost about $6,000 to $7,000, and the additional monthly supplies for the pump are also expensive.

If patients are engaged when considering and selecting insulin therapy, the likelihood of treatment success is greater.^26–28

Insulin therapy is one of the most effective tools clinicians can use to help patients reach their individualized hemoglobin A_1c target. However, decisions about when and how to start insulin therapy have to be individualized to the needs and goals of each patient. Many insulin options are available, one of the most common being the addition of basal insulin to oral antidiabetic drugs. Although patients are often reluctant to start insulin, this reluctance can be overcome through patient education and hands-on training.

Here, we review hemoglobin A_1c targets, factors that determine when to start insulin therapy, and the different regimens that can be used.

MOST PATIENTS EVENTUALLY NEED INSULIN

Type 2 diabetes mellitus is a chronic progressive disease associated with insulin resistance, beta-cell dysfunction, and decreased insulin secretion. Consequently, most patients eventually require insulin therapy to reduce the risk of long-term complications.

The efficacy of therapy can be assessed by measuring hemoglobin A_1c, an important marker of the chronic hyperglycemic state. The hemoglobin A_1c value can be reported as a ratio (%) standardized against the results of the Diabetes Control and Complications Trial,¹ or as International Federation of Clinical Chemistry units (mmol/mol).² Table 1 shows the relationship between hemoglobin A_1c and average glucose values.³

WHAT IS AN APPROPRIATE HEMOGLOBIN A_1c TARGET?

The short answer is, “It depends.”

Currently, the American Association of Clinical Endocrinologists (AACE) supports a hemoglobin A_1c goal of less than 6.5% for otherwise healthy patients but states that the goal should be individualized for patients with concurrent illnesses or at risk of hypoglycemia.⁴

On the other hand, the American Diabetes Association (ADA) recommends a higher hemoglobin A_1c target of less than 7% for most adults with type 2 diabetes mellitus.⁵ This value was shown to be associated with a reduction in the microvascular and macrovascular complications of diabetes.

Yet when three large trials^6–8 recently compared intensive and standard glucose control regimens, tighter glucose control failed to improve cardiovascular outcomes. Moreover, in one of the trials,⁷ patients receiving intensive treatment had a higher rate of all-cause mortality. Details:

• Action in Diabetes and Vascular Disease (ADVANCE): 11,140 patients; average hemoglobin A_1c levels 6.5% vs 7.3%⁶
• Action to Control Cardiovascular Risk in Diabetes (ACCORD): 10,251 patients; average hemoglobin A_1c levels 6.4% vs 7.5%⁷
• Veterans Affairs Diabetes Trial (VADT): 1,791 patients; average hemoglobin A_1c levels 6.9% vs 8.4%.⁸

Similarly, a 2013 Cochrane review⁹ that included 28 randomized controlled trials concluded that intensive control (in 18,717 patients) did not decrease all-cause and cardiovascular mortality rates compared with traditional glucose control (in 16,195 patients), and it increased the risk of hypoglycemia and serious adverse events.

The AACE and ADA are moving away from one-size-fits-all and toward individualized recommendations

As a result, the ADA⁵ states that a hemoglobin A_1c target less than 6.5% is optional for patients with a long life expectancy, short duration of diabetes, low risk of hypoglycemia, and no significant cardiovascular disease. The ADA further defines a hemoglobin A_1c goal of less than 8% for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, and long-standing diabetes.

Therefore, the AACE and ADA are moving away from “one-size-fits-all” goals and toward individualizing their recommendations.

WHEN SHOULD INSULIN BE STARTED?

Physicians should consider the needs and preferences of each patient and individualize the treatment. The most recent recommendations from the ADA⁵ stress the importance of a patient-centered approach, with multiple factors taken into account. These include the patient’s attitude, expected compliance with treatment, risk of hypoglycemia, disease duration, life expectancy, and comorbidities, and the side effects of oral medications and insulin.

Compared with previous guidelines, there are fewer rules on how and when to start insulin therapy. But absolute and relative indications for insulin therapy should be considered in patients with the following:

Absolute indications for insulin

• Ketoacidosis or catabolic symptoms, including ketonuria
• Newly diagnosed type 2 diabetes with pronounced hyperglycemia (glucose ≥ 300 mg/dL or hemoglobin A_1c ≥ 10.0%) with or without severe symptoms, including weight loss, polyuria, or polydipsia¹⁰
• Uncontrolled type 2 diabetes mellitus despite using one, two, or more oral antidiabetic drugs or glucagon-like peptide 1 (GLP-1) receptor agonists
• Gestational diabetes
• Preference for insulin.

Relative indications for insulin

• Hospitalized for surgery or acute illnesses
• Advanced renal or hepatic disease
• Inability to afford the cost or tolerate the side effects of oral antidiabetic drugs and GLP-1 receptor agonists.

Depending on the situation, blood glucose is measured fasting, before meals, or after meals after initiating or adjusting insulin regimens (Table 2).

WHAT ARE THE INSULIN REGIMENS?

Basal insulin

In the early stages of type 2 diabetes, metformin alone or in combination with another oral antidiabetic drug or with a GLP-1 receptor agonist is often used along with healthy eating, weight control, and increased physical activity.

When the target hemoglobin A_1c cannot be achieved with one or two noninsulin drugs, the ADA suggests basal insulin be added to metformin or a two-medication regimen that includes metformin (Table 3). However, recent evidence suggests that combining a GLP-1 receptor agonist with basal insulin, in a regimen without metformin, is safe and improves glycemic control without hypoglycemia or weight gain.¹¹

While a total daily dose of insulin of 0.1 to 0.2 units/kg could be initially used in patients with a hemoglobin A_1c level less than 8%, a higher dose of 0.2 to 0.3 units/kg is required if the hemoglobin A_1c level is between 8% and 10%. The dose can be titrated once or twice weekly if the fasting glucose is above the target level (usually < 130 mg/dL). If hypoglycemia develops (glucose < 70 mg/dL), the insulin dose should be reduced by 10% to 20%.¹⁰

Available basal insulins include glargine, detemir, and neutral protamine Hagedorn (NPH) (Table 4).^12–14 Because glargine and detemir offer better pharmacokinetic properties, less variability in response, and less risk of hypoglycemia, they are preferred over NPH. Glargine has a relatively constant plasma concentration over 24 hours, allowing once-daily dosing at any time during the day (Figure 1).¹⁵ The dose should be taken at the same time every day. Detemir and NPH are usually taken once or twice daily.

Adapted from Hirsch IB. Insulin analogues. N Engl J Med 2005; 352:174-183. Copyright 2005, Massachusetts Medical Society.

Patients treated once daily should take the dose with the evening meal or at bedtime. Patients who require a twice-daily regimen can take the first dose with breakfast and the second one with the evening meal, at bedtime, or 12 hours after the morning dose.

The randomized Treat-to-Target trial,¹⁶ in 756 patients, showed that both glargine and NPH, when added to oral therapy in patients with type 2 diabetes, achieve the target hemoglobin A_1c, but NPH is associated with more episodes of nocturnal hypoglycemia. Similar results were found when NPH was compared with detemir insulin.¹⁷

A Cochrane review¹⁸ suggested that glargine and detemir are similar in efficacy and safety. However, detemir often needs to be injected twice daily, in a higher dose, and is associated with less weight gain. Furthermore, a meta-analysis of 46 randomized clinical trials¹⁹ showed that the weight increase at 1 year is less in patients treated with basal than with twice-daily or prandial regimens.

The ADA suggests basal insulin be added to metformin alone or a regimen that includes metformin

A noninterventional longitudinal study²⁰ in 2,179 patients newly started on insulin showed that the mean weight increase at 1 year was 1.78 kg, and 24% of patients gained more than 5 kg. However, the factors independently associated with the weight gain were a higher hemoglobin A_1c at baseline, a higher insulin dose at baseline and at 1 year, and a lower baseline body mass index, but not the type of insulin regimen.

Currently, a new class of ultralong-acting basal insulins is being studied. Insulins in this class are approved in other countries, but the US Food and Drug Administration requires additional data for approval. Ultralong-acting insulins are expected to reduce the risk of hypoglycemia, specifically the risk of nocturnal episodes. Also, given their longer duration of action and stable steady-state pharmacokinetics, they will offer flexibility in the dose timing.²¹

Basal-bolus regimens

Basal insulin often does not control postprandial hyperglycemia. The need for multiple doses of insulin (including one or more preprandial doses) is suggested by postprandial glucose values above target (usually > 180 mg/dL) or by a hemoglobin A_1c above goal despite well-controlled fasting glucose levels. This usually becomes evident when the total daily dose of basal insulin exceeds 0.5 units/kg. Patients newly diagnosed with diabetes who have a hemoglobin A_1c higher than 10% may also respond better to an initial basal-bolus regimen.

Available bolus insulins include lispro, aspart, glulisine, regular insulin, and the newly approved Technosphere inhaled regular insulin (Table 4).^12–14 They can be taken before each meal, and the total bolus dose usually represents 50% of the total daily dose.²² Rapid-acting insulins have faster onset, shorter duration of action, and more predictable pharmacokinetics, which makes them preferable to regular insulin (Figure 1).¹⁵ Inhaled insulin is another option, but it is contraindicated in patients with chronic obstructive pulmonary disease or asthma because of the increased risk of acute bronchospasm.¹²

Alternatively, the transition to a basal-bolus regimen can be accomplished with a single dose of bolus insulin before the main meal, using a dose that represents approximately 10% of the total daily dose. Additional bolus doses can be added later based on the glycemic control. The adjustment of the preprandial insulin dose is done once or twice weekly, based on the postprandial glucose levels.¹⁰

Premixed combinations of long- and short-acting insulins in ratios of 50% to 50%, 70% to 30%, or 75% to 25% can be considered in patients who cannot adhere to a complex insulin regimen. A propensity-matched comparison of different insulin regimens (basal, premixed, mealtime plus basal, and mealtime) in patients with type 2 diabetes revealed that the hemoglobin A_1c reduction was similar between the different groups.²³ However, the number of hypoglycemic episodes was higher in the premixed insulin group, and the weight gain was less in the basal insulin group.

While premixed insulins require fewer injections, they do not provide dosing flexibility. In other words, dose adjustments for premixed insulins lead to increases in both basal and bolus amounts even though a dose adjustment is needed for only one insulin type. Thus, this is a common reason for increased hypoglycemic episodes.

Continuous subcutaneous insulin infusion

Patients who are engaged in their care are more likely to succeed in their treatment

A meta-analysis showed that continuous subcutaneous insulin infusion (ie, use of an insulin pump) was similar to intensive therapy with multiple daily insulin injections in terms of glycemic control and hypoglycemia.²⁴ Since both options can lead to similar glucose control, additional factors to consider when initiating insulin infusion include lifestyle and technical expertise. Some patients may or may not prefer having a pump attached for nearly all daily activities. Additionally, this type of therapy is complex and requires significant training to ensure efficacy and safety.²⁵

WHAT IS THE COST OF INSULIN THERAPY?

A final factor to keep in mind when initiating insulin is cost (Table 4).^12–14 Asking patients to check their prescription insurance formulary is important to ensure that an affordable option is selected. If patients do not have prescription insurance, medication assistance programs could be an option. However, if a patient is considering an insulin pump, insurance coverage is essential. Depending on the manufacturer, insulin pumps cost about $6,000 to $7,000, and the additional monthly supplies for the pump are also expensive.

If patients are engaged when considering and selecting insulin therapy, the likelihood of treatment success is greater.^26–28

Insulin therapy is one of the most effective tools clinicians can use to help patients reach their individualized hemoglobin A_1c target. However, decisions about when and how to start insulin therapy have to be individualized to the needs and goals of each patient. Many insulin options are available, one of the most common being the addition of basal insulin to oral antidiabetic drugs. Although patients are often reluctant to start insulin, this reluctance can be overcome through patient education and hands-on training.

Here, we review hemoglobin A_1c targets, factors that determine when to start insulin therapy, and the different regimens that can be used.

MOST PATIENTS EVENTUALLY NEED INSULIN

Type 2 diabetes mellitus is a chronic progressive disease associated with insulin resistance, beta-cell dysfunction, and decreased insulin secretion. Consequently, most patients eventually require insulin therapy to reduce the risk of long-term complications.

The efficacy of therapy can be assessed by measuring hemoglobin A_1c, an important marker of the chronic hyperglycemic state. The hemoglobin A_1c value can be reported as a ratio (%) standardized against the results of the Diabetes Control and Complications Trial,¹ or as International Federation of Clinical Chemistry units (mmol/mol).² Table 1 shows the relationship between hemoglobin A_1c and average glucose values.³

WHAT IS AN APPROPRIATE HEMOGLOBIN A_1c TARGET?

The short answer is, “It depends.”

Currently, the American Association of Clinical Endocrinologists (AACE) supports a hemoglobin A_1c goal of less than 6.5% for otherwise healthy patients but states that the goal should be individualized for patients with concurrent illnesses or at risk of hypoglycemia.⁴

On the other hand, the American Diabetes Association (ADA) recommends a higher hemoglobin A_1c target of less than 7% for most adults with type 2 diabetes mellitus.⁵ This value was shown to be associated with a reduction in the microvascular and macrovascular complications of diabetes.

Yet when three large trials^6–8 recently compared intensive and standard glucose control regimens, tighter glucose control failed to improve cardiovascular outcomes. Moreover, in one of the trials,⁷ patients receiving intensive treatment had a higher rate of all-cause mortality. Details:

• Action in Diabetes and Vascular Disease (ADVANCE): 11,140 patients; average hemoglobin A_1c levels 6.5% vs 7.3%⁶
• Action to Control Cardiovascular Risk in Diabetes (ACCORD): 10,251 patients; average hemoglobin A_1c levels 6.4% vs 7.5%⁷
• Veterans Affairs Diabetes Trial (VADT): 1,791 patients; average hemoglobin A_1c levels 6.9% vs 8.4%.⁸

Similarly, a 2013 Cochrane review⁹ that included 28 randomized controlled trials concluded that intensive control (in 18,717 patients) did not decrease all-cause and cardiovascular mortality rates compared with traditional glucose control (in 16,195 patients), and it increased the risk of hypoglycemia and serious adverse events.

The AACE and ADA are moving away from one-size-fits-all and toward individualized recommendations

As a result, the ADA⁵ states that a hemoglobin A_1c target less than 6.5% is optional for patients with a long life expectancy, short duration of diabetes, low risk of hypoglycemia, and no significant cardiovascular disease. The ADA further defines a hemoglobin A_1c goal of less than 8% for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, and long-standing diabetes.

Therefore, the AACE and ADA are moving away from “one-size-fits-all” goals and toward individualizing their recommendations.

WHEN SHOULD INSULIN BE STARTED?

Physicians should consider the needs and preferences of each patient and individualize the treatment. The most recent recommendations from the ADA⁵ stress the importance of a patient-centered approach, with multiple factors taken into account. These include the patient’s attitude, expected compliance with treatment, risk of hypoglycemia, disease duration, life expectancy, and comorbidities, and the side effects of oral medications and insulin.

Compared with previous guidelines, there are fewer rules on how and when to start insulin therapy. But absolute and relative indications for insulin therapy should be considered in patients with the following:

Absolute indications for insulin

• Ketoacidosis or catabolic symptoms, including ketonuria
• Newly diagnosed type 2 diabetes with pronounced hyperglycemia (glucose ≥ 300 mg/dL or hemoglobin A_1c ≥ 10.0%) with or without severe symptoms, including weight loss, polyuria, or polydipsia¹⁰
• Uncontrolled type 2 diabetes mellitus despite using one, two, or more oral antidiabetic drugs or glucagon-like peptide 1 (GLP-1) receptor agonists
• Gestational diabetes
• Preference for insulin.

Relative indications for insulin

• Hospitalized for surgery or acute illnesses
• Advanced renal or hepatic disease
• Inability to afford the cost or tolerate the side effects of oral antidiabetic drugs and GLP-1 receptor agonists.

Depending on the situation, blood glucose is measured fasting, before meals, or after meals after initiating or adjusting insulin regimens (Table 2).

WHAT ARE THE INSULIN REGIMENS?

Basal insulin

In the early stages of type 2 diabetes, metformin alone or in combination with another oral antidiabetic drug or with a GLP-1 receptor agonist is often used along with healthy eating, weight control, and increased physical activity.

When the target hemoglobin A_1c cannot be achieved with one or two noninsulin drugs, the ADA suggests basal insulin be added to metformin or a two-medication regimen that includes metformin (Table 3). However, recent evidence suggests that combining a GLP-1 receptor agonist with basal insulin, in a regimen without metformin, is safe and improves glycemic control without hypoglycemia or weight gain.¹¹

While a total daily dose of insulin of 0.1 to 0.2 units/kg could be initially used in patients with a hemoglobin A_1c level less than 8%, a higher dose of 0.2 to 0.3 units/kg is required if the hemoglobin A_1c level is between 8% and 10%. The dose can be titrated once or twice weekly if the fasting glucose is above the target level (usually < 130 mg/dL). If hypoglycemia develops (glucose < 70 mg/dL), the insulin dose should be reduced by 10% to 20%.¹⁰

Available basal insulins include glargine, detemir, and neutral protamine Hagedorn (NPH) (Table 4).^12–14 Because glargine and detemir offer better pharmacokinetic properties, less variability in response, and less risk of hypoglycemia, they are preferred over NPH. Glargine has a relatively constant plasma concentration over 24 hours, allowing once-daily dosing at any time during the day (Figure 1).¹⁵ The dose should be taken at the same time every day. Detemir and NPH are usually taken once or twice daily.

Adapted from Hirsch IB. Insulin analogues. N Engl J Med 2005; 352:174-183. Copyright 2005, Massachusetts Medical Society.

Patients treated once daily should take the dose with the evening meal or at bedtime. Patients who require a twice-daily regimen can take the first dose with breakfast and the second one with the evening meal, at bedtime, or 12 hours after the morning dose.

The randomized Treat-to-Target trial,¹⁶ in 756 patients, showed that both glargine and NPH, when added to oral therapy in patients with type 2 diabetes, achieve the target hemoglobin A_1c, but NPH is associated with more episodes of nocturnal hypoglycemia. Similar results were found when NPH was compared with detemir insulin.¹⁷

A Cochrane review¹⁸ suggested that glargine and detemir are similar in efficacy and safety. However, detemir often needs to be injected twice daily, in a higher dose, and is associated with less weight gain. Furthermore, a meta-analysis of 46 randomized clinical trials¹⁹ showed that the weight increase at 1 year is less in patients treated with basal than with twice-daily or prandial regimens.

The ADA suggests basal insulin be added to metformin alone or a regimen that includes metformin

A noninterventional longitudinal study²⁰ in 2,179 patients newly started on insulin showed that the mean weight increase at 1 year was 1.78 kg, and 24% of patients gained more than 5 kg. However, the factors independently associated with the weight gain were a higher hemoglobin A_1c at baseline, a higher insulin dose at baseline and at 1 year, and a lower baseline body mass index, but not the type of insulin regimen.

Currently, a new class of ultralong-acting basal insulins is being studied. Insulins in this class are approved in other countries, but the US Food and Drug Administration requires additional data for approval. Ultralong-acting insulins are expected to reduce the risk of hypoglycemia, specifically the risk of nocturnal episodes. Also, given their longer duration of action and stable steady-state pharmacokinetics, they will offer flexibility in the dose timing.²¹

Basal-bolus regimens

Basal insulin often does not control postprandial hyperglycemia. The need for multiple doses of insulin (including one or more preprandial doses) is suggested by postprandial glucose values above target (usually > 180 mg/dL) or by a hemoglobin A_1c above goal despite well-controlled fasting glucose levels. This usually becomes evident when the total daily dose of basal insulin exceeds 0.5 units/kg. Patients newly diagnosed with diabetes who have a hemoglobin A_1c higher than 10% may also respond better to an initial basal-bolus regimen.

Available bolus insulins include lispro, aspart, glulisine, regular insulin, and the newly approved Technosphere inhaled regular insulin (Table 4).^12–14 They can be taken before each meal, and the total bolus dose usually represents 50% of the total daily dose.²² Rapid-acting insulins have faster onset, shorter duration of action, and more predictable pharmacokinetics, which makes them preferable to regular insulin (Figure 1).¹⁵ Inhaled insulin is another option, but it is contraindicated in patients with chronic obstructive pulmonary disease or asthma because of the increased risk of acute bronchospasm.¹²

Alternatively, the transition to a basal-bolus regimen can be accomplished with a single dose of bolus insulin before the main meal, using a dose that represents approximately 10% of the total daily dose. Additional bolus doses can be added later based on the glycemic control. The adjustment of the preprandial insulin dose is done once or twice weekly, based on the postprandial glucose levels.¹⁰

Premixed combinations of long- and short-acting insulins in ratios of 50% to 50%, 70% to 30%, or 75% to 25% can be considered in patients who cannot adhere to a complex insulin regimen. A propensity-matched comparison of different insulin regimens (basal, premixed, mealtime plus basal, and mealtime) in patients with type 2 diabetes revealed that the hemoglobin A_1c reduction was similar between the different groups.²³ However, the number of hypoglycemic episodes was higher in the premixed insulin group, and the weight gain was less in the basal insulin group.

While premixed insulins require fewer injections, they do not provide dosing flexibility. In other words, dose adjustments for premixed insulins lead to increases in both basal and bolus amounts even though a dose adjustment is needed for only one insulin type. Thus, this is a common reason for increased hypoglycemic episodes.

Continuous subcutaneous insulin infusion

Patients who are engaged in their care are more likely to succeed in their treatment

A meta-analysis showed that continuous subcutaneous insulin infusion (ie, use of an insulin pump) was similar to intensive therapy with multiple daily insulin injections in terms of glycemic control and hypoglycemia.²⁴ Since both options can lead to similar glucose control, additional factors to consider when initiating insulin infusion include lifestyle and technical expertise. Some patients may or may not prefer having a pump attached for nearly all daily activities. Additionally, this type of therapy is complex and requires significant training to ensure efficacy and safety.²⁵

WHAT IS THE COST OF INSULIN THERAPY?

A final factor to keep in mind when initiating insulin is cost (Table 4).^12–14 Asking patients to check their prescription insurance formulary is important to ensure that an affordable option is selected. If patients do not have prescription insurance, medication assistance programs could be an option. However, if a patient is considering an insulin pump, insurance coverage is essential. Depending on the manufacturer, insulin pumps cost about $6,000 to $7,000, and the additional monthly supplies for the pump are also expensive.

If patients are engaged when considering and selecting insulin therapy, the likelihood of treatment success is greater.^26–28

A 57-year-old man hospitalized for treatment of multilobar pneumonia was noted to have a rapid, irregular heart rate on telemetry. He was hypoxemic and appeared to be in respiratory distress. A 12-lead electrocardiogram (ECG) demonstrated atrial fibrillation with rapid ventricular response, as well as what looked like distinct and regular P waves dissociated from the QRS complexes at a rate of about 44/min (Figure 1). What is the explanation and clinical significance of this curious finding?

What appear to be dissociated P waves actually represent respiratory artifact.^1–3 The sharp deflections mimicking P waves signify the tonic initiation of inspiratory effort; the subsequent brief periods of low-amplitude, high-frequency micro-oscillations represent surface electrical activity associated with the increased force of the accessory muscles of respiration.^1–3

Surface electromyography noninvasively measures muscle activity using electrodes placed on the skin overlying the muscle.⁴ Using simultaneously recorded mechanical respiratory waveform tracings, we have previously demonstrated that the repetitive pseudo-P waves followed by micro-oscillations have a close temporal relationship with the inspiratory phase of respiration.³ The presence of respiratory artifact indicates a high-risk state frequently necessitating ventilation support.

In addition, when present, respiratory artifact can be viewed as the “second vital sign” on the ECG, the first vital sign being the heart rate. The respiratory rate can be approximated by counting the number of respiratory artifacts in a 10-second recording and multiplying it by 6. A more accurate rate assessment is achieved by measuring 1 or more respiratory artifact cycles in millimeters and then dividing that number into 1,500 or its multiples.³ Based on these calculations, the respiratory rate in this patient was 44/min.

The presence of two atrial rhythms on the same ECG, one not disturbing the other, is consistent with the diagnosis of atrial dissociation.⁵ Atrial dissociation is a common finding in cardiac transplant recipients in whom the transplantation was performed using atrio-atrial anastomosis.⁶ Most other cases of apparent atrial dissociation described in the old cardiology and critical care literature probably represented unrecognized respiratory artifact.^7,8

An ECG from a different patient (Figure 2) demonstrates rapid respiratory artifact that raised awareness of severe respiratory failure. The respiratory rate calculated from spacing of the pseudo-P waves is 62/min, confirmed by simultaneous respirography.

A FREQUENT FINDING IN SICK HOSPITALIZED PATIENTS

Respiratory artifact is a frequent finding in sick hospitalized patients.³ Most commonly, it manifests as repetitive micro-oscillations.³ Pseudo-P waves, as in this 57-year-old patient, are less often observed; but if their origin is not recognized, the interpretation of the ECG can become puzzling.^1–3,7,8

Respiratory artifact is a marker of increased work of breathing and a strong indicator of significant cardiopulmonary compromise. Improvement in the patient’s cardiac or respiratory condition is typically associated with a decrease in the rate or complete elimination of respiratory artifact.³

Recognition of rapid respiratory artifact is less important in critical care units, where patients’ vital signs and cardiorespiratory status are carefully observed. However, in hospital settings where respiratory rate and oxygen saturation are not continuously monitored, recognizing rapid respiratory artifact can help raise awareness of the possibility of severe respiratory distress.

A 57-year-old man hospitalized for treatment of multilobar pneumonia was noted to have a rapid, irregular heart rate on telemetry. He was hypoxemic and appeared to be in respiratory distress. A 12-lead electrocardiogram (ECG) demonstrated atrial fibrillation with rapid ventricular response, as well as what looked like distinct and regular P waves dissociated from the QRS complexes at a rate of about 44/min (Figure 1). What is the explanation and clinical significance of this curious finding?

What appear to be dissociated P waves actually represent respiratory artifact.^1–3 The sharp deflections mimicking P waves signify the tonic initiation of inspiratory effort; the subsequent brief periods of low-amplitude, high-frequency micro-oscillations represent surface electrical activity associated with the increased force of the accessory muscles of respiration.^1–3

Surface electromyography noninvasively measures muscle activity using electrodes placed on the skin overlying the muscle.⁴ Using simultaneously recorded mechanical respiratory waveform tracings, we have previously demonstrated that the repetitive pseudo-P waves followed by micro-oscillations have a close temporal relationship with the inspiratory phase of respiration.³ The presence of respiratory artifact indicates a high-risk state frequently necessitating ventilation support.

In addition, when present, respiratory artifact can be viewed as the “second vital sign” on the ECG, the first vital sign being the heart rate. The respiratory rate can be approximated by counting the number of respiratory artifacts in a 10-second recording and multiplying it by 6. A more accurate rate assessment is achieved by measuring 1 or more respiratory artifact cycles in millimeters and then dividing that number into 1,500 or its multiples.³ Based on these calculations, the respiratory rate in this patient was 44/min.

The presence of two atrial rhythms on the same ECG, one not disturbing the other, is consistent with the diagnosis of atrial dissociation.⁵ Atrial dissociation is a common finding in cardiac transplant recipients in whom the transplantation was performed using atrio-atrial anastomosis.⁶ Most other cases of apparent atrial dissociation described in the old cardiology and critical care literature probably represented unrecognized respiratory artifact.^7,8

An ECG from a different patient (Figure 2) demonstrates rapid respiratory artifact that raised awareness of severe respiratory failure. The respiratory rate calculated from spacing of the pseudo-P waves is 62/min, confirmed by simultaneous respirography.

A FREQUENT FINDING IN SICK HOSPITALIZED PATIENTS

Respiratory artifact is a frequent finding in sick hospitalized patients.³ Most commonly, it manifests as repetitive micro-oscillations.³ Pseudo-P waves, as in this 57-year-old patient, are less often observed; but if their origin is not recognized, the interpretation of the ECG can become puzzling.^1–3,7,8

Respiratory artifact is a marker of increased work of breathing and a strong indicator of significant cardiopulmonary compromise. Improvement in the patient’s cardiac or respiratory condition is typically associated with a decrease in the rate or complete elimination of respiratory artifact.³

Recognition of rapid respiratory artifact is less important in critical care units, where patients’ vital signs and cardiorespiratory status are carefully observed. However, in hospital settings where respiratory rate and oxygen saturation are not continuously monitored, recognizing rapid respiratory artifact can help raise awareness of the possibility of severe respiratory distress.

A 57-year-old man hospitalized for treatment of multilobar pneumonia was noted to have a rapid, irregular heart rate on telemetry. He was hypoxemic and appeared to be in respiratory distress. A 12-lead electrocardiogram (ECG) demonstrated atrial fibrillation with rapid ventricular response, as well as what looked like distinct and regular P waves dissociated from the QRS complexes at a rate of about 44/min (Figure 1). What is the explanation and clinical significance of this curious finding?

What appear to be dissociated P waves actually represent respiratory artifact.^1–3 The sharp deflections mimicking P waves signify the tonic initiation of inspiratory effort; the subsequent brief periods of low-amplitude, high-frequency micro-oscillations represent surface electrical activity associated with the increased force of the accessory muscles of respiration.^1–3

Surface electromyography noninvasively measures muscle activity using electrodes placed on the skin overlying the muscle.⁴ Using simultaneously recorded mechanical respiratory waveform tracings, we have previously demonstrated that the repetitive pseudo-P waves followed by micro-oscillations have a close temporal relationship with the inspiratory phase of respiration.³ The presence of respiratory artifact indicates a high-risk state frequently necessitating ventilation support.

In addition, when present, respiratory artifact can be viewed as the “second vital sign” on the ECG, the first vital sign being the heart rate. The respiratory rate can be approximated by counting the number of respiratory artifacts in a 10-second recording and multiplying it by 6. A more accurate rate assessment is achieved by measuring 1 or more respiratory artifact cycles in millimeters and then dividing that number into 1,500 or its multiples.³ Based on these calculations, the respiratory rate in this patient was 44/min.

The presence of two atrial rhythms on the same ECG, one not disturbing the other, is consistent with the diagnosis of atrial dissociation.⁵ Atrial dissociation is a common finding in cardiac transplant recipients in whom the transplantation was performed using atrio-atrial anastomosis.⁶ Most other cases of apparent atrial dissociation described in the old cardiology and critical care literature probably represented unrecognized respiratory artifact.^7,8

An ECG from a different patient (Figure 2) demonstrates rapid respiratory artifact that raised awareness of severe respiratory failure. The respiratory rate calculated from spacing of the pseudo-P waves is 62/min, confirmed by simultaneous respirography.

A FREQUENT FINDING IN SICK HOSPITALIZED PATIENTS

Respiratory artifact is a frequent finding in sick hospitalized patients.³ Most commonly, it manifests as repetitive micro-oscillations.³ Pseudo-P waves, as in this 57-year-old patient, are less often observed; but if their origin is not recognized, the interpretation of the ECG can become puzzling.^1–3,7,8

Respiratory artifact is a marker of increased work of breathing and a strong indicator of significant cardiopulmonary compromise. Improvement in the patient’s cardiac or respiratory condition is typically associated with a decrease in the rate or complete elimination of respiratory artifact.³

Recognition of rapid respiratory artifact is less important in critical care units, where patients’ vital signs and cardiorespiratory status are carefully observed. However, in hospital settings where respiratory rate and oxygen saturation are not continuously monitored, recognizing rapid respiratory artifact can help raise awareness of the possibility of severe respiratory distress.

Guidelines for the management of chronic disease are starting to recognize vulnerable elderly patients. The topics in this review, culled from recent studies and recommendations, were chosen because they may change geriatric care. They include the newest influenza and pneumococcal vaccines; recommendations for managing chronic heart failure, cholesterol, and blood pressure; preventing frailty; drug treatments for dementia; and the impact of cognitive impairment on health outcomes.

INFLUENZA VACCINATION: HIGH-DOSE SUPERIOR BUT COSTLIER

Three classes of influenza vaccines have been available for some time:

• The standard-dose, trivalent inactivated injectable vaccine (IIV3-SD) contains H1N1, H3N2, and influenza B strains and is approved for all ages over 6 months.
• The quadrivalent vaccine (available mostly for nasal administration) has the same strains as the trivalent vaccine plus a second, different influenza B strain. The inactivated vaccine is injectable for all persons over the age of 6 months; the live-attenuated vaccine is available as a nasal spray only for ages 2 through 49.
• The high-dose injectable vaccine (IIV3-HD) contains the same strains as the trivalent vaccine plus four times as much hemagglutinin—the influenza virus antigen that stimulates immunity.

Although IIV3-HD has been available since 2010, no clinical data existed until 2014 showing it to be superior to standard-dose vaccine.

DiazGranados et al¹ randomized nearly 32,000 adults age 65 and older to receive either the standard-dose or the high-dose vaccine. The primary end point was laboratory-confirmed influenza caused by any influenza viral type or subtype, in association with a protocol-defined influenzalike illness.

The primary end point was reached in 1.4% of those with the high-dose vaccine and 1.9% of those with the standard-dose vaccine (relative efficacy 24.2%, 95% confidence interval 9.7–36.5). There was also a 26% reduction in respiratory illness regardless of laboratory confirmation. Mortality rates were identical and low (0.5%) in both groups. In those without laboratory confirmation of respiratory illness, there was a 26% lower rate of pneumonia but no statistical difference in rates of hospitalization, medication use, routine office visits, and emergency department visits.

These results can be interpreted as meaning that the high-dose vaccine prevented about a quarter of the laboratory-confirmed influenza cases that would have occurred with the standard-dose vaccine. However, due to the low rate of disease in those given the standard-dose vaccine, the number needed to treat to prevent one influenza infection was about 200 with the high-dose vs the standard-dose vaccine; to prevent one case of pneumonia, more than 270 would need to be treated.

The current price differential as well as the high number needed to treat to prevent one infection may discourage the use of the high-dose vaccine. Medicare Part B pays for one dose of either influenza vaccine per season. For patients who paid out of pocket, the 2014–2015 season cost at a typical pharmacy was about $32 for the standard-dose vaccine and $55 for the high-dose.

PNEUMOCOCCAL VACCINATION

Conjugate vaccine now recommended for seniors

The 23-valent polysaccharide vaccine (Pneumovax) has been available since 1983 and is recommended in the United States for all adults age 65 and over. A 13-valent pneumococcal diphtheria conjugate vaccine (Prevnar 13) has been available since 2010. Until recently, the conjugate vaccine was recommended for children; the only adults for whom it was recommended were those age 19 and over who either were immunocompromised or had a cochlear implant, asplenia, a cerebral spinal fluid leak, or renal failure.

The CAPITA trial² (Community-Acquired Pneumonia Immunisation Trial in Adults) randomized nearly 85,000 people (most 65 and older, and some children) in the Netherlands to receive either the conjugate vaccine or placebo. It found a 46% reduction in community-acquired pneumonia (P = .0006), a 45% reduction in nonbacteremic nonvaccine-type community-acquired pneumonia (P = .0067), and a 75% reduction in vaccine-type invasive pneumococcal disease (P = .0005). Common side effects included pain, swelling at the injection site, limitation of arm movement, fatigue, headache, decreased appetite, chills, and rash.

Based on this one study, the Advisory Committee on Immunization Practices³ recommended that all adults 65 and older receive the conjugate vaccine.

The recommendations for the conjugate vaccine for all ages are complicated. Limited to those age 65 and older, current recommendations are:

• For those who have already received the polysaccharide vaccine: get the conjugated vaccine at least 1 year later
• For those who have never received the polysaccharide vaccine: get the conjugate vaccine now, then the polysaccharide vaccine 6 to 12 months later.

Number needed to treat with the high-dose vs the standard-dose vaccine to prevent one case of
influenza: 200

Whether the Netherlands findings fully apply to the United States is under question. At the time of the study, Dutch infants but not adults had received pneumonia conjugate vaccinations since 2002 with a high compliance rate. Unlike in the United States, the polysaccharide pneumococcal vaccine had not been routinely recommended in the Netherlands. There may have been some indirect immunity due to the “herd” effect, but no direct immunity. With a likely higher background immunity to pneumonia in the United States, the dramatic reduction in infection noted in the Netherlands may not be duplicated here.

For those without Medicare coverage, the 2014–2015 winter season cost at a pharmacy was about $95 for the polysaccharide vaccine and about $200 for the conjugate vaccine. As of February 2, 2015, the Centers for Medicare and Medicaid Services are implementing Medicare Part B coverage to allow initial pneumococcal vaccine for Medicare patients who never received a pneumococcal vaccine under Medicare Part B, and then a different, second pneumococcal vaccine, 1 year after the first vaccine was administered.

HEART FAILURE

Eplerenone’s new role in mild heart failure

Aldosterone antagonists have been recommended for moderate to severe heart failure (New York Heart Association [NYHA] classes III and IV) for some time. The 2013 American College of Cardiology/American Heart Association  (ACC/AHA) guidelines also recommend them for mild heart failure (NYHA II).⁴

The EMPHASIS trial⁵ (Eplerenone in Patients With Systolic Heart Failure and Mild Symptoms) randomized 2,737 patients, median age 69, with NYHA class II heart failure and an ejection fraction of no more than 35% to receive the aldosterone antagonist eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. The trial was stopped early, after a median follow-up of 21 months, when the treatment group was found to have a significantly lower risk of cardiovascular death or hospitalization for heart failure or for any cause.

Of note: hyperkalemia occurred in 11.8% of the eplerenone group vs 7.2% in the placebo group (P < .001). The high frequency of hyperkalemia in the placebo group may have been due to concomitant use of angiotensin-converting enzyme (ACE) inhibitors.

Sodium restriction reasonable

Although sodium restriction has been standard practice in heart failure for decades, restricting sodium in the elderly was given only a IIa (“reasonable”) classification, based on level C (very limited) evidence.⁴

2013 ACC/AHA guidelines recommend aldosterone antagonism for mild heart failure

Strong evidence exists that middle-aged and young older adults with heart failure (with preserved or reduced ejection fraction) should reduce their sodium intake by about 1 g per day or aim for a mean 24-hour urinary sodium excretion of about 2.3 g per day. However, little evidence exists to support a specific long-term target intake, and no evidence exists for “old-old” patients (loosely defined as older than 75 or 80).

Caution with digoxin

Use of digoxin has been recommended in patients with heart failure with reduced ejection fraction to reduce hospitalizations,⁴ but more recent publications have raised questions regarding its safety and efficacy.

Freeman et al,⁶ in a prospective study, followed 2,891 patients with newly diagnosed systolic heart failure over 2.5 years, of whom 529 were prescribed digoxin. The digoxin group had a higher rate of death (14.2 vs 11.2 per 100 patient-years) and heart failure-related hospitalization (28.2 vs 24.4 per 100 person-years).

The study was unable to determine if the digoxin level influenced the results, since about 30% of patients had no digoxin level drawn, and an additional 27% had only one level drawn during the study. For those with measured blood levels, the mean digoxin level for men was 0.83 ng/mL and 1.12 ng/mL for women. Risks and benefits of this medication should be weighed carefully.

Simultaneous interventions beneficial

The following evidence-based interventions are recommended for patients with heart failure with reduced ejection fraction:

• Heart failure education
• A beta-blocker
• An ACE inhibitor
• An aldosterone antagonist for NYHA class II–IV symptoms
• Anticoagulation for atrial fibrillation in patients with added risks (eg, hypertension, diabetes, prior transient ischemic attack or cerebrovascular accident, age at least 75)
• An implantable cardioverter-defibrillator and cardiac resynchronization therapy for select patients with symptoms, increased QRS duration, and left bundle branch block.

Fonarow et al⁷ studied these interventions in an analysis of a prospective study of outpatients with diagnosed heart failure or myocardial infarction and reduced left ventricular ejection fraction. Their nested case-control study compared 1,376 patients, mean age 72, who had died within 24 months and 2,752 propensity-matched controls who survived to 24 months. The survival rate was 37% higher with two simultaneous interventions than with one, and 70% higher with four simultaneous interventions than with one. Benefits plateaued with four to five interventions.

LIPID-LOWERING THERAPY FOR SENIORS

The 2013 ACC/AHA cholesterol guideline⁸ included new recommendations specifically relevant to the elderly. It advocates using a new cardiovascular disease risk calculator that provides an estimate of 10-year risk of atherosclerotic cardiovascular disease (ASCVD), based on data from multiple community-based populations and applicable to African American and non-Hispanic white men and women ages 40 through 79. Primary prevention with a statin is encouraged for those with a 10-year risk of 7.5% or higher. The tool generated controversy from the moment it was announced and may overestimate ASCVD risk by 67% in women and 86% in men.⁹

Emphasis on tolerability

The guideline focuses on statins as the main treatment and de-emphasizes the adjunctive use of other drugs to further lower lipids such as niacin, ezetimibe, and fenofibrate.

Statin tolerability is now stressed rather than specific lipid level targets. The guideline recommends reassessing statin choice and intensity according to pain, tenderness, stiffness, cramping, weakness, and fatigue (class IIa recommendation [“reasonable”], level of evidence B [“limited”]). Also recommended is reassessment of statin choice and intensity for patients older than 75 or for those taking multiple medications, drugs that alter metabolism, and conditions requiring complex medications (class IIa, level of evidence C [“very limited”]). For patients with confusion, statin and nonstatin causes should be considered as the source of the problem (class IIb [“consider”], level of evidence C).

Initiating high-intensity statin therapy is not recommended after age 75. However, continuing such treatment is reasonable for patients already receiving and tolerating the therapy for an appropriate indication. Initiation of moderate-intensity statin therapy in this age group is recommended for those with either clinical atherosclerotic cardiovascular disease or a low-density lipoprotein cholesterol (LDL-C) level of at least 190 mg/dL.

Statin tolerability is now stressed rather than specific lipid level targets

No specific guidance is provided for patients older than age 75 without ASCVD, with LDL-C less than 190 mg/dL, or with diabetes. In these groups, statin therapy may be initiated, continued, or intensified (class IIb, level of evidence C).

HYPERTENSION: LESS AGGRESSIVE GOALS FOR ELDERLY

The eighth Joint National Committee (JNC 8)¹⁰ made nine recommendations for managing high blood pressure, only one of which specifically addresses people 60 and older.

Drug therapy should be initiated if the blood pressure is 150/90 mm Hg or higher, and the blood pressure should be treated to less than that level (grade A recommendation, ie, strong). If treated systolic blood pressure is less than 140 mm Hg without adverse effects, it should be sustained (grade E recommendation, ie, based on expert opinion).

Tension between guidelines

The higher threshold for hypertension treatment and the lower threshold for statin therapy create tension between guidelines, and between guidelines and epidemiologic data.

For example, in a 67-year-old woman without diabetes and with a favorable lipid profile (eg, total cholesterol 130 mg/dL, high-density lipoprotein cholesterol 55 mg/dL), the ACC/AHA ASCVD risk calculator predicts a 10-year risk of less than 7.5% if her systolic blood pressure is 147 mm Hg. If the patient’s blood pressure were 148 or 149 mm Hg and all the other variables were the same, the JNC 8 would not recommend treatment with antihypertensive medication, but the ACC/AHA guidelines would recommend preventive statin therapy.

Another example is the relationship between heart failure and antihypertensive drugs. Multiple studies^11,12 demonstrate a reduction in heart failure incidence with hypertension treatment. A 70-year-old man whose systolic blood pressure is 140 mm Hg has about a 15% lifetime risk of heart failure. If his systolic pressure were 160 mm Hg, his lifetime heart failure risk would be more than 50%.¹³ If his systolic pressure were 149, his lifetime risk of heart failure would be between 15% and 50%, but the JNC 8 criteria do not recommend antihypertensive therapy.

EXERCISE SLOWS PROGRESSION TO FRAILTY

In the absence of a gold standard, frailty has been operationally defined as meeting three out of five phenotypic criteria: diminished grip strength, low energy, slow gait, low physical activity, and unintentional weight loss. A “prefrail” stage, in which one or two criteria are present, identifies a vulnerable subset at high risk of progression to frailty.

About 42% of older adults in the community are considered vulnerable, or prefrail, and about 11% are frail.¹⁴ Interventions at the prefrail stage may prevent progression to frailty, but it is rare, without intervention, for a person to re-achieve the stronger stage once diagnosed with frailty.

Pahor et al¹⁵ randomized 1,635 sedentary adults ages 70 to 89 who met the criteria of prefrailty to either a moderate-intensity exercise program (consisting of aerobic, resistance, and flexibility exercises for 150 minutes per week, performed in a center and at home) or to a health education program with workshops on topics relevant to older adults and upper-extremity stretching exercises. Adherence to the exercise program was verified by questionnaire and an accelerometer device. Participants were assessed every 6 months for an average of 2.6 years.

The primary outcome measure was the development of major mobility disability as defined by the loss of ability to walk 400 m without assistance (a cane was acceptable, but not a walker). The primary outcome occurred in 30.1% of those in the exercise group and 35.5% of the health education group (hazard ratio 0.82, P = .03). Those in the exercise group also had one third fewer falls. No differences were found in death rates. The number needed to treat was about 19 to prevent one person from developing major disability. Those most likely to benefit were those who walked slowly at baseline (< 1.8 mph), were more mobility-impaired, and were more cognitively healthy.

SLOWING DEMENTIA IS STILL AN ELUSIVE GOAL

Vitamin E modestly improves cognitive function but may have a cost

Before new information emerged in 2014 regarding vitamin E and dementia, the best data were from a 1997 study¹⁶ that randomized patients with moderate dementia to either daily vitamin E 2,000 IU, the monoamine oxidase inhibitor selegiline 10 mg, both, or placebo for 2 years. No benefit of treatment for cognitive function was found. However, after adjusting for the baseline Mini-Mental State Examination score, the investigators found that either treatment was associated with a delay of about 7 months in the primary outcome (death, institutionalization, loss of activities of daily living, or severe dementia).

About 42% of community-dwelling older adults are considered ‘prefrail,’ and 11% are frail

Unfortunately, selegiline is often poorly tolerated, causing dyskinesia in more than 10% of patients, nausea in 20%, and confusion, hallucinations, and syncope. Although vitamin E is better tolerated, in high doses it can cause fatigue, headache, and bleeding, with increased risk of hemorrhagic stroke. Studies conflict as to whether it increases the risk of death from any cause.^17,18

Dysken et al,¹⁹ in a study reported in 2014, randomized 613 patients with mild to moderate Alzheimer disease, all of whom were taking an acetylcholinesterase inhibitor, to either daily vitamin E 2,000 IU, memantine 20 mg, both, or placebo. The primary outcome measure was an activities of daily living score (0–78, higher being better), which included the ability to perform such tasks as dressing oneself. Each task was scored from 0 (totally dependent on help) to 4 (able to perform completely independently).

Scores fell in both groups over the mean 2.7 years of the study, but the decrease was slightly slower in the vitamin E group: 3 points less at the end of the study compared with placebo. The groups taking memantine, vitamin E, or both did not differ significantly from one another. No significant differences were found in the secondary outcome of cognitive, neuropsychiatric, functional, and caregiver measures.

Based on the 1997 study, vitamin E may defer the time to important clinical outcomes by 7.5 months over a 2-year period in patients with moderate dementia. Based on the 2014 study, vitamin E may preserve half an activity of daily living over 2.7 years in patients with mild to moderate dementia. On the other hand, high doses of vitamin E may increase the risk of bleeding and falling, and whether they increase the risk of death is unclear.

Antidepressants for behavior issues

Other common problems in patients with major neurocognitive disorders include disturbed perception, thought content, mood, and behavior, collectively called behavioral and psychological symptoms of dementia. No known nondrug intervention is consistently effective for these problems, and no drug approved by the US Food and Drug Administration (FDA), except for a fixed-dose combination of dextromethorphan and quinidine, addresses any specific symptom.

Porsteinsson et al²⁰ randomized 186 patients with Alzheimer disease and agitation to a psychological intervention plus either the selective serotonin reuptake inhibitor citalopram (titrated from 10 to 30 mg per day based on response and tolerability) or placebo. Agitation was reduced with citalopram compared with placebo, based on the agitation subscale of the Neurobehavioral Rating Scale.

Of those taking citalopram, 40% were much or very much improved, compared with 26% of those taking placebo. These results are comparable to or better than those with antipsychotic drugs, which should be avoided for treating dementia-related psychosis in elderly patients because of black-box warnings.

No differences were found in activities of daily living. An interesting finding, not seen in other studies, is that the Mini-Mental Status Examination score declined by 1 point in the treatment group vs no change in the placebo group (P = .03).

Although vitamin E may delay important outcomes in dementia, high doses may increase the risk of bleeding and falling

Prolonged QTc was found in 12.5% in the citalopram group vs 4.3% in the placebo group (P = .01). The FDA issued a warning in 2012 of a dose-dependent effect of citalopram on QTc and recommended a maximum dose of 20 mg for those over age 60; for “poor metabolizers” of cytochrome P450 2C19 (CYP 2C19); and for those taking medications that inhibit CYP 2C19, including proton pump inhibitors, cimetidine, fluvoxamine, fluoxetine, indomethacin, ketoconazole, modafinil, and probenecid. The United Kingdom has extended this warning to escitalopram. Unfortunately, in the Porsteinsson study, nearly 80% of the treatment group received the 30-mg dose and only 15% received the 20-mg dose, which provided insufficient data for independent analysis.

Possibly, citalopram cannot be administered in a dosage sufficient to produce the benefits seen in the study. Using escitalopram may also be risky. Based on this study, it would be prudent to monitor QTc when using these drugs.

Dextromethorphan and quinidine

A fixed-dose combination of dextromethorphan and quinidine (Nuedexta) was recently approved by the FDA for treatment of pseudobulbar affect in individuals with stroke, traumatic brain injury, or dementia. Pseudobulbar affect has been defined as a condition of contextually inappropriate or exaggerated emotional expression that often occurs in adults with neurologic damage.

Using a 20/10-mg dose combination, a small 12-week noncomparative trial demonstrated measurable improvement in pseudobulbar symptoms after 30 days (as measured by the Center for Neurologic Study-Lability Scale).²¹ Though individuals enrolled in this trial appeared to tolerate this dose, additional trials still need to be conducted to more clearly determine its long-term safety and efficacy. It is not approved for dementia with agitation, but a phase 2 trial suggests a benefit compared with placebo in reducing agitation and caregiver burden.²²

RISKS OF MILD COGNITIVE IMPAIRMENT

The spectrum of cognitive impairment ranges from mild cognitive impairment (MCI), in which deficits are evident on neuropsychological testing but the person maintains overall function, to the different stages of dementia (mild, moderate, and severe). MCI was documented in the Cardiovascular Health Study in 22% of adults 75 and older.²³

Despite presenting with apparently normal function, elderly people with MCI have a higher risk of falls, rehospitalization, and delirium. Screening is not typically performed for MCI in primary care. No study has compared clinical outcomes after screening vs not screening for cognitive impairment (whether MCI or dementia), and the US Preventive Services Task Force maintains that there is insufficient evidence for screening.²⁴

Unrecognized cognitive impairment affects discharge outcomes

Nazir et al,²⁵ in a 1-year longitudinal study, compared 976 patients age 65 and older who upon admission to a public hospital were either diagnosed with cognitive impairment (defined as scoring 7 or less on the 10-question Short Portable Mental Status Questionnaire) or not. They found that 42.5% were cognitively impaired on admission. Overall, 36.5% of patients were discharged to a facility rather than home; those who were cognitively impaired, older, and sicker were more likely to be discharged to a facility.

The elderly population is heterogeneous

Interestingly, among those discharged to a facility, patients with cognitive impairment were less likely to be subsequently rehospitalized or die within 30 days of hospital discharge than those without cognitive impairment. Whether this can be explained by differences in comorbidities between the groups was not explored. Those discharged home had similar rates of death and rehospitalization whether or not they were cognitively impaired.

Patel et al²⁶ screened 720 older patients upon discharge after hospitalization for heart failure with the Mini-Cog (a 3-minute test that consists of recall of three words and the ability to draw a clock face). About a quarter of patients were diagnosed with cognitive impairment based on this test.

Among those discharged home (about two-thirds of the group overall), patients were much more likely to be rehospitalized or die within 30 days if they were cognitively impaired. Among those discharged to a facility, the rates between the two groups were similar for the first 20 days; after that, people in the cognitively impaired group were much more likely to die or be readmitted to a hospital.

Dodson et al,²⁷ in a study of 282 hospitalized patients with heart failure (mean age 80), identified 47% as having cognitive impairment at the time of hospitalization based on a score of less than 25 on the Mini-Mental State Examination. Of those found to have mild cognitive impairment (score 21–24), only 11% had documentation of a cognitive deficit in the medical record, and 39% of those found to have moderate to severe cognitive impairment (score < 21) had documentation of it in the medical record. Those with unrecognized impairment were 1.5 times more likely to die or be rehospitalized within 6 months than those with documented impairment.

Do interventions help?

It is unclear whether developing specific interventions tailored to cognitive impairment improves outcomes.

Davis et al²⁸ studied 125 patients hospitalized for heart failure who were identified as having mild cognitive impairment based on a Montreal Cognitive Assessment score of 17 to 25 (out of 30) points. Patients were randomly assigned to either a targeted self-care teaching intervention or usual discharge care. The intervention included education and customized instruction on self-care tasks such as managing symptoms, organizing medications, and measuring fluid and sodium intake.

Thirty days after discharge, the intervention group had greater knowledge about heart failure than the control group, but no significant difference was found in ability to care for themselves or in readmission rates.

Interventions that target the patient-caregiver dyad may have more success. A pilot project in Indiana²⁹ that developed an integrative care model for older people with mild cognitive impairment, dementia, or depression that targeted patients as well as their caregivers found that compared with patients from area primary care clinics, their patients had lower rehospitalization rates within 30 days of discharge (11% vs 20%) and higher rates of achieving a hemoglobin A_1c of less than 8% (78% vs 51%). Results of an expanded innovations demonstration project awarded by the Centers for Medicare and Medicaid Services are pending.

The following more recently published data show promise for prevention of dementia through nonpharmacologic interventions.

The FINGER trial³⁰ (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) screened 2,654 Finnish individuals ages 60 to 77 using the Cardiovascular Risk Factors, Aging and Dementia risk tool, identifying 1,260 individuals with higher levels of cognitive impairment and randomizing them to a 2-year intervention consisting of exercise, cognitive training, and vascular risk monitoring (n = 631), or a control group provided with general health advice only (n = 629). Neuropsychological testing was conducted to measure differences between the groups, and at the end of the study, the mean Z-score difference in the total testing score between the intervention and control group was 0.22 (P = .30). This trial demonstrated that if cognitive impairment were identified, a multimodal intervention could improve or maintain cognitive function in at-risk elderly individuals.

Guidelines for the management of chronic disease are starting to recognize vulnerable elderly patients. The topics in this review, culled from recent studies and recommendations, were chosen because they may change geriatric care. They include the newest influenza and pneumococcal vaccines; recommendations for managing chronic heart failure, cholesterol, and blood pressure; preventing frailty; drug treatments for dementia; and the impact of cognitive impairment on health outcomes.

INFLUENZA VACCINATION: HIGH-DOSE SUPERIOR BUT COSTLIER

Three classes of influenza vaccines have been available for some time:

• The standard-dose, trivalent inactivated injectable vaccine (IIV3-SD) contains H1N1, H3N2, and influenza B strains and is approved for all ages over 6 months.
• The quadrivalent vaccine (available mostly for nasal administration) has the same strains as the trivalent vaccine plus a second, different influenza B strain. The inactivated vaccine is injectable for all persons over the age of 6 months; the live-attenuated vaccine is available as a nasal spray only for ages 2 through 49.
• The high-dose injectable vaccine (IIV3-HD) contains the same strains as the trivalent vaccine plus four times as much hemagglutinin—the influenza virus antigen that stimulates immunity.

Although IIV3-HD has been available since 2010, no clinical data existed until 2014 showing it to be superior to standard-dose vaccine.

DiazGranados et al¹ randomized nearly 32,000 adults age 65 and older to receive either the standard-dose or the high-dose vaccine. The primary end point was laboratory-confirmed influenza caused by any influenza viral type or subtype, in association with a protocol-defined influenzalike illness.

The primary end point was reached in 1.4% of those with the high-dose vaccine and 1.9% of those with the standard-dose vaccine (relative efficacy 24.2%, 95% confidence interval 9.7–36.5). There was also a 26% reduction in respiratory illness regardless of laboratory confirmation. Mortality rates were identical and low (0.5%) in both groups. In those without laboratory confirmation of respiratory illness, there was a 26% lower rate of pneumonia but no statistical difference in rates of hospitalization, medication use, routine office visits, and emergency department visits.

These results can be interpreted as meaning that the high-dose vaccine prevented about a quarter of the laboratory-confirmed influenza cases that would have occurred with the standard-dose vaccine. However, due to the low rate of disease in those given the standard-dose vaccine, the number needed to treat to prevent one influenza infection was about 200 with the high-dose vs the standard-dose vaccine; to prevent one case of pneumonia, more than 270 would need to be treated.

The current price differential as well as the high number needed to treat to prevent one infection may discourage the use of the high-dose vaccine. Medicare Part B pays for one dose of either influenza vaccine per season. For patients who paid out of pocket, the 2014–2015 season cost at a typical pharmacy was about $32 for the standard-dose vaccine and $55 for the high-dose.

PNEUMOCOCCAL VACCINATION

Conjugate vaccine now recommended for seniors

The 23-valent polysaccharide vaccine (Pneumovax) has been available since 1983 and is recommended in the United States for all adults age 65 and over. A 13-valent pneumococcal diphtheria conjugate vaccine (Prevnar 13) has been available since 2010. Until recently, the conjugate vaccine was recommended for children; the only adults for whom it was recommended were those age 19 and over who either were immunocompromised or had a cochlear implant, asplenia, a cerebral spinal fluid leak, or renal failure.

The CAPITA trial² (Community-Acquired Pneumonia Immunisation Trial in Adults) randomized nearly 85,000 people (most 65 and older, and some children) in the Netherlands to receive either the conjugate vaccine or placebo. It found a 46% reduction in community-acquired pneumonia (P = .0006), a 45% reduction in nonbacteremic nonvaccine-type community-acquired pneumonia (P = .0067), and a 75% reduction in vaccine-type invasive pneumococcal disease (P = .0005). Common side effects included pain, swelling at the injection site, limitation of arm movement, fatigue, headache, decreased appetite, chills, and rash.

Based on this one study, the Advisory Committee on Immunization Practices³ recommended that all adults 65 and older receive the conjugate vaccine.

The recommendations for the conjugate vaccine for all ages are complicated. Limited to those age 65 and older, current recommendations are:

• For those who have already received the polysaccharide vaccine: get the conjugated vaccine at least 1 year later
• For those who have never received the polysaccharide vaccine: get the conjugate vaccine now, then the polysaccharide vaccine 6 to 12 months later.

Number needed to treat with the high-dose vs the standard-dose vaccine to prevent one case of
influenza: 200

Whether the Netherlands findings fully apply to the United States is under question. At the time of the study, Dutch infants but not adults had received pneumonia conjugate vaccinations since 2002 with a high compliance rate. Unlike in the United States, the polysaccharide pneumococcal vaccine had not been routinely recommended in the Netherlands. There may have been some indirect immunity due to the “herd” effect, but no direct immunity. With a likely higher background immunity to pneumonia in the United States, the dramatic reduction in infection noted in the Netherlands may not be duplicated here.

For those without Medicare coverage, the 2014–2015 winter season cost at a pharmacy was about $95 for the polysaccharide vaccine and about $200 for the conjugate vaccine. As of February 2, 2015, the Centers for Medicare and Medicaid Services are implementing Medicare Part B coverage to allow initial pneumococcal vaccine for Medicare patients who never received a pneumococcal vaccine under Medicare Part B, and then a different, second pneumococcal vaccine, 1 year after the first vaccine was administered.

HEART FAILURE

Eplerenone’s new role in mild heart failure

Aldosterone antagonists have been recommended for moderate to severe heart failure (New York Heart Association [NYHA] classes III and IV) for some time. The 2013 American College of Cardiology/American Heart Association  (ACC/AHA) guidelines also recommend them for mild heart failure (NYHA II).⁴

The EMPHASIS trial⁵ (Eplerenone in Patients With Systolic Heart Failure and Mild Symptoms) randomized 2,737 patients, median age 69, with NYHA class II heart failure and an ejection fraction of no more than 35% to receive the aldosterone antagonist eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. The trial was stopped early, after a median follow-up of 21 months, when the treatment group was found to have a significantly lower risk of cardiovascular death or hospitalization for heart failure or for any cause.

Of note: hyperkalemia occurred in 11.8% of the eplerenone group vs 7.2% in the placebo group (P < .001). The high frequency of hyperkalemia in the placebo group may have been due to concomitant use of angiotensin-converting enzyme (ACE) inhibitors.

Sodium restriction reasonable

Although sodium restriction has been standard practice in heart failure for decades, restricting sodium in the elderly was given only a IIa (“reasonable”) classification, based on level C (very limited) evidence.⁴

2013 ACC/AHA guidelines recommend aldosterone antagonism for mild heart failure

Strong evidence exists that middle-aged and young older adults with heart failure (with preserved or reduced ejection fraction) should reduce their sodium intake by about 1 g per day or aim for a mean 24-hour urinary sodium excretion of about 2.3 g per day. However, little evidence exists to support a specific long-term target intake, and no evidence exists for “old-old” patients (loosely defined as older than 75 or 80).

Caution with digoxin

Use of digoxin has been recommended in patients with heart failure with reduced ejection fraction to reduce hospitalizations,⁴ but more recent publications have raised questions regarding its safety and efficacy.

Freeman et al,⁶ in a prospective study, followed 2,891 patients with newly diagnosed systolic heart failure over 2.5 years, of whom 529 were prescribed digoxin. The digoxin group had a higher rate of death (14.2 vs 11.2 per 100 patient-years) and heart failure-related hospitalization (28.2 vs 24.4 per 100 person-years).

The study was unable to determine if the digoxin level influenced the results, since about 30% of patients had no digoxin level drawn, and an additional 27% had only one level drawn during the study. For those with measured blood levels, the mean digoxin level for men was 0.83 ng/mL and 1.12 ng/mL for women. Risks and benefits of this medication should be weighed carefully.

Simultaneous interventions beneficial

The following evidence-based interventions are recommended for patients with heart failure with reduced ejection fraction:

• Heart failure education
• A beta-blocker
• An ACE inhibitor
• An aldosterone antagonist for NYHA class II–IV symptoms
• Anticoagulation for atrial fibrillation in patients with added risks (eg, hypertension, diabetes, prior transient ischemic attack or cerebrovascular accident, age at least 75)
• An implantable cardioverter-defibrillator and cardiac resynchronization therapy for select patients with symptoms, increased QRS duration, and left bundle branch block.

Fonarow et al⁷ studied these interventions in an analysis of a prospective study of outpatients with diagnosed heart failure or myocardial infarction and reduced left ventricular ejection fraction. Their nested case-control study compared 1,376 patients, mean age 72, who had died within 24 months and 2,752 propensity-matched controls who survived to 24 months. The survival rate was 37% higher with two simultaneous interventions than with one, and 70% higher with four simultaneous interventions than with one. Benefits plateaued with four to five interventions.

LIPID-LOWERING THERAPY FOR SENIORS

The 2013 ACC/AHA cholesterol guideline⁸ included new recommendations specifically relevant to the elderly. It advocates using a new cardiovascular disease risk calculator that provides an estimate of 10-year risk of atherosclerotic cardiovascular disease (ASCVD), based on data from multiple community-based populations and applicable to African American and non-Hispanic white men and women ages 40 through 79. Primary prevention with a statin is encouraged for those with a 10-year risk of 7.5% or higher. The tool generated controversy from the moment it was announced and may overestimate ASCVD risk by 67% in women and 86% in men.⁹

Emphasis on tolerability

The guideline focuses on statins as the main treatment and de-emphasizes the adjunctive use of other drugs to further lower lipids such as niacin, ezetimibe, and fenofibrate.

Statin tolerability is now stressed rather than specific lipid level targets. The guideline recommends reassessing statin choice and intensity according to pain, tenderness, stiffness, cramping, weakness, and fatigue (class IIa recommendation [“reasonable”], level of evidence B [“limited”]). Also recommended is reassessment of statin choice and intensity for patients older than 75 or for those taking multiple medications, drugs that alter metabolism, and conditions requiring complex medications (class IIa, level of evidence C [“very limited”]). For patients with confusion, statin and nonstatin causes should be considered as the source of the problem (class IIb [“consider”], level of evidence C).

Initiating high-intensity statin therapy is not recommended after age 75. However, continuing such treatment is reasonable for patients already receiving and tolerating the therapy for an appropriate indication. Initiation of moderate-intensity statin therapy in this age group is recommended for those with either clinical atherosclerotic cardiovascular disease or a low-density lipoprotein cholesterol (LDL-C) level of at least 190 mg/dL.

Statin tolerability is now stressed rather than specific lipid level targets

No specific guidance is provided for patients older than age 75 without ASCVD, with LDL-C less than 190 mg/dL, or with diabetes. In these groups, statin therapy may be initiated, continued, or intensified (class IIb, level of evidence C).

HYPERTENSION: LESS AGGRESSIVE GOALS FOR ELDERLY

The eighth Joint National Committee (JNC 8)¹⁰ made nine recommendations for managing high blood pressure, only one of which specifically addresses people 60 and older.

Drug therapy should be initiated if the blood pressure is 150/90 mm Hg or higher, and the blood pressure should be treated to less than that level (grade A recommendation, ie, strong). If treated systolic blood pressure is less than 140 mm Hg without adverse effects, it should be sustained (grade E recommendation, ie, based on expert opinion).

Tension between guidelines

The higher threshold for hypertension treatment and the lower threshold for statin therapy create tension between guidelines, and between guidelines and epidemiologic data.

For example, in a 67-year-old woman without diabetes and with a favorable lipid profile (eg, total cholesterol 130 mg/dL, high-density lipoprotein cholesterol 55 mg/dL), the ACC/AHA ASCVD risk calculator predicts a 10-year risk of less than 7.5% if her systolic blood pressure is 147 mm Hg. If the patient’s blood pressure were 148 or 149 mm Hg and all the other variables were the same, the JNC 8 would not recommend treatment with antihypertensive medication, but the ACC/AHA guidelines would recommend preventive statin therapy.

Another example is the relationship between heart failure and antihypertensive drugs. Multiple studies^11,12 demonstrate a reduction in heart failure incidence with hypertension treatment. A 70-year-old man whose systolic blood pressure is 140 mm Hg has about a 15% lifetime risk of heart failure. If his systolic pressure were 160 mm Hg, his lifetime heart failure risk would be more than 50%.¹³ If his systolic pressure were 149, his lifetime risk of heart failure would be between 15% and 50%, but the JNC 8 criteria do not recommend antihypertensive therapy.

EXERCISE SLOWS PROGRESSION TO FRAILTY

In the absence of a gold standard, frailty has been operationally defined as meeting three out of five phenotypic criteria: diminished grip strength, low energy, slow gait, low physical activity, and unintentional weight loss. A “prefrail” stage, in which one or two criteria are present, identifies a vulnerable subset at high risk of progression to frailty.

About 42% of older adults in the community are considered vulnerable, or prefrail, and about 11% are frail.¹⁴ Interventions at the prefrail stage may prevent progression to frailty, but it is rare, without intervention, for a person to re-achieve the stronger stage once diagnosed with frailty.

Pahor et al¹⁵ randomized 1,635 sedentary adults ages 70 to 89 who met the criteria of prefrailty to either a moderate-intensity exercise program (consisting of aerobic, resistance, and flexibility exercises for 150 minutes per week, performed in a center and at home) or to a health education program with workshops on topics relevant to older adults and upper-extremity stretching exercises. Adherence to the exercise program was verified by questionnaire and an accelerometer device. Participants were assessed every 6 months for an average of 2.6 years.

The primary outcome measure was the development of major mobility disability as defined by the loss of ability to walk 400 m without assistance (a cane was acceptable, but not a walker). The primary outcome occurred in 30.1% of those in the exercise group and 35.5% of the health education group (hazard ratio 0.82, P = .03). Those in the exercise group also had one third fewer falls. No differences were found in death rates. The number needed to treat was about 19 to prevent one person from developing major disability. Those most likely to benefit were those who walked slowly at baseline (< 1.8 mph), were more mobility-impaired, and were more cognitively healthy.

SLOWING DEMENTIA IS STILL AN ELUSIVE GOAL

Vitamin E modestly improves cognitive function but may have a cost

Before new information emerged in 2014 regarding vitamin E and dementia, the best data were from a 1997 study¹⁶ that randomized patients with moderate dementia to either daily vitamin E 2,000 IU, the monoamine oxidase inhibitor selegiline 10 mg, both, or placebo for 2 years. No benefit of treatment for cognitive function was found. However, after adjusting for the baseline Mini-Mental State Examination score, the investigators found that either treatment was associated with a delay of about 7 months in the primary outcome (death, institutionalization, loss of activities of daily living, or severe dementia).

About 42% of community-dwelling older adults are considered ‘prefrail,’ and 11% are frail

Unfortunately, selegiline is often poorly tolerated, causing dyskinesia in more than 10% of patients, nausea in 20%, and confusion, hallucinations, and syncope. Although vitamin E is better tolerated, in high doses it can cause fatigue, headache, and bleeding, with increased risk of hemorrhagic stroke. Studies conflict as to whether it increases the risk of death from any cause.^17,18

Dysken et al,¹⁹ in a study reported in 2014, randomized 613 patients with mild to moderate Alzheimer disease, all of whom were taking an acetylcholinesterase inhibitor, to either daily vitamin E 2,000 IU, memantine 20 mg, both, or placebo. The primary outcome measure was an activities of daily living score (0–78, higher being better), which included the ability to perform such tasks as dressing oneself. Each task was scored from 0 (totally dependent on help) to 4 (able to perform completely independently).

Scores fell in both groups over the mean 2.7 years of the study, but the decrease was slightly slower in the vitamin E group: 3 points less at the end of the study compared with placebo. The groups taking memantine, vitamin E, or both did not differ significantly from one another. No significant differences were found in the secondary outcome of cognitive, neuropsychiatric, functional, and caregiver measures.

Based on the 1997 study, vitamin E may defer the time to important clinical outcomes by 7.5 months over a 2-year period in patients with moderate dementia. Based on the 2014 study, vitamin E may preserve half an activity of daily living over 2.7 years in patients with mild to moderate dementia. On the other hand, high doses of vitamin E may increase the risk of bleeding and falling, and whether they increase the risk of death is unclear.

Antidepressants for behavior issues

Other common problems in patients with major neurocognitive disorders include disturbed perception, thought content, mood, and behavior, collectively called behavioral and psychological symptoms of dementia. No known nondrug intervention is consistently effective for these problems, and no drug approved by the US Food and Drug Administration (FDA), except for a fixed-dose combination of dextromethorphan and quinidine, addresses any specific symptom.

Porsteinsson et al²⁰ randomized 186 patients with Alzheimer disease and agitation to a psychological intervention plus either the selective serotonin reuptake inhibitor citalopram (titrated from 10 to 30 mg per day based on response and tolerability) or placebo. Agitation was reduced with citalopram compared with placebo, based on the agitation subscale of the Neurobehavioral Rating Scale.

Of those taking citalopram, 40% were much or very much improved, compared with 26% of those taking placebo. These results are comparable to or better than those with antipsychotic drugs, which should be avoided for treating dementia-related psychosis in elderly patients because of black-box warnings.

No differences were found in activities of daily living. An interesting finding, not seen in other studies, is that the Mini-Mental Status Examination score declined by 1 point in the treatment group vs no change in the placebo group (P = .03).

Although vitamin E may delay important outcomes in dementia, high doses may increase the risk of bleeding and falling

Prolonged QTc was found in 12.5% in the citalopram group vs 4.3% in the placebo group (P = .01). The FDA issued a warning in 2012 of a dose-dependent effect of citalopram on QTc and recommended a maximum dose of 20 mg for those over age 60; for “poor metabolizers” of cytochrome P450 2C19 (CYP 2C19); and for those taking medications that inhibit CYP 2C19, including proton pump inhibitors, cimetidine, fluvoxamine, fluoxetine, indomethacin, ketoconazole, modafinil, and probenecid. The United Kingdom has extended this warning to escitalopram. Unfortunately, in the Porsteinsson study, nearly 80% of the treatment group received the 30-mg dose and only 15% received the 20-mg dose, which provided insufficient data for independent analysis.

Possibly, citalopram cannot be administered in a dosage sufficient to produce the benefits seen in the study. Using escitalopram may also be risky. Based on this study, it would be prudent to monitor QTc when using these drugs.

Dextromethorphan and quinidine

A fixed-dose combination of dextromethorphan and quinidine (Nuedexta) was recently approved by the FDA for treatment of pseudobulbar affect in individuals with stroke, traumatic brain injury, or dementia. Pseudobulbar affect has been defined as a condition of contextually inappropriate or exaggerated emotional expression that often occurs in adults with neurologic damage.

Using a 20/10-mg dose combination, a small 12-week noncomparative trial demonstrated measurable improvement in pseudobulbar symptoms after 30 days (as measured by the Center for Neurologic Study-Lability Scale).²¹ Though individuals enrolled in this trial appeared to tolerate this dose, additional trials still need to be conducted to more clearly determine its long-term safety and efficacy. It is not approved for dementia with agitation, but a phase 2 trial suggests a benefit compared with placebo in reducing agitation and caregiver burden.²²

RISKS OF MILD COGNITIVE IMPAIRMENT

The spectrum of cognitive impairment ranges from mild cognitive impairment (MCI), in which deficits are evident on neuropsychological testing but the person maintains overall function, to the different stages of dementia (mild, moderate, and severe). MCI was documented in the Cardiovascular Health Study in 22% of adults 75 and older.²³

Despite presenting with apparently normal function, elderly people with MCI have a higher risk of falls, rehospitalization, and delirium. Screening is not typically performed for MCI in primary care. No study has compared clinical outcomes after screening vs not screening for cognitive impairment (whether MCI or dementia), and the US Preventive Services Task Force maintains that there is insufficient evidence for screening.²⁴

Unrecognized cognitive impairment affects discharge outcomes

Nazir et al,²⁵ in a 1-year longitudinal study, compared 976 patients age 65 and older who upon admission to a public hospital were either diagnosed with cognitive impairment (defined as scoring 7 or less on the 10-question Short Portable Mental Status Questionnaire) or not. They found that 42.5% were cognitively impaired on admission. Overall, 36.5% of patients were discharged to a facility rather than home; those who were cognitively impaired, older, and sicker were more likely to be discharged to a facility.

The elderly population is heterogeneous

Interestingly, among those discharged to a facility, patients with cognitive impairment were less likely to be subsequently rehospitalized or die within 30 days of hospital discharge than those without cognitive impairment. Whether this can be explained by differences in comorbidities between the groups was not explored. Those discharged home had similar rates of death and rehospitalization whether or not they were cognitively impaired.

Patel et al²⁶ screened 720 older patients upon discharge after hospitalization for heart failure with the Mini-Cog (a 3-minute test that consists of recall of three words and the ability to draw a clock face). About a quarter of patients were diagnosed with cognitive impairment based on this test.

Among those discharged home (about two-thirds of the group overall), patients were much more likely to be rehospitalized or die within 30 days if they were cognitively impaired. Among those discharged to a facility, the rates between the two groups were similar for the first 20 days; after that, people in the cognitively impaired group were much more likely to die or be readmitted to a hospital.

Dodson et al,²⁷ in a study of 282 hospitalized patients with heart failure (mean age 80), identified 47% as having cognitive impairment at the time of hospitalization based on a score of less than 25 on the Mini-Mental State Examination. Of those found to have mild cognitive impairment (score 21–24), only 11% had documentation of a cognitive deficit in the medical record, and 39% of those found to have moderate to severe cognitive impairment (score < 21) had documentation of it in the medical record. Those with unrecognized impairment were 1.5 times more likely to die or be rehospitalized within 6 months than those with documented impairment.

Do interventions help?

It is unclear whether developing specific interventions tailored to cognitive impairment improves outcomes.

Davis et al²⁸ studied 125 patients hospitalized for heart failure who were identified as having mild cognitive impairment based on a Montreal Cognitive Assessment score of 17 to 25 (out of 30) points. Patients were randomly assigned to either a targeted self-care teaching intervention or usual discharge care. The intervention included education and customized instruction on self-care tasks such as managing symptoms, organizing medications, and measuring fluid and sodium intake.

Thirty days after discharge, the intervention group had greater knowledge about heart failure than the control group, but no significant difference was found in ability to care for themselves or in readmission rates.

Interventions that target the patient-caregiver dyad may have more success. A pilot project in Indiana²⁹ that developed an integrative care model for older people with mild cognitive impairment, dementia, or depression that targeted patients as well as their caregivers found that compared with patients from area primary care clinics, their patients had lower rehospitalization rates within 30 days of discharge (11% vs 20%) and higher rates of achieving a hemoglobin A_1c of less than 8% (78% vs 51%). Results of an expanded innovations demonstration project awarded by the Centers for Medicare and Medicaid Services are pending.

The following more recently published data show promise for prevention of dementia through nonpharmacologic interventions.

The FINGER trial³⁰ (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) screened 2,654 Finnish individuals ages 60 to 77 using the Cardiovascular Risk Factors, Aging and Dementia risk tool, identifying 1,260 individuals with higher levels of cognitive impairment and randomizing them to a 2-year intervention consisting of exercise, cognitive training, and vascular risk monitoring (n = 631), or a control group provided with general health advice only (n = 629). Neuropsychological testing was conducted to measure differences between the groups, and at the end of the study, the mean Z-score difference in the total testing score between the intervention and control group was 0.22 (P = .30). This trial demonstrated that if cognitive impairment were identified, a multimodal intervention could improve or maintain cognitive function in at-risk elderly individuals.

Guidelines for the management of chronic disease are starting to recognize vulnerable elderly patients. The topics in this review, culled from recent studies and recommendations, were chosen because they may change geriatric care. They include the newest influenza and pneumococcal vaccines; recommendations for managing chronic heart failure, cholesterol, and blood pressure; preventing frailty; drug treatments for dementia; and the impact of cognitive impairment on health outcomes.

INFLUENZA VACCINATION: HIGH-DOSE SUPERIOR BUT COSTLIER

Three classes of influenza vaccines have been available for some time:

• The standard-dose, trivalent inactivated injectable vaccine (IIV3-SD) contains H1N1, H3N2, and influenza B strains and is approved for all ages over 6 months.
• The quadrivalent vaccine (available mostly for nasal administration) has the same strains as the trivalent vaccine plus a second, different influenza B strain. The inactivated vaccine is injectable for all persons over the age of 6 months; the live-attenuated vaccine is available as a nasal spray only for ages 2 through 49.
• The high-dose injectable vaccine (IIV3-HD) contains the same strains as the trivalent vaccine plus four times as much hemagglutinin—the influenza virus antigen that stimulates immunity.

Although IIV3-HD has been available since 2010, no clinical data existed until 2014 showing it to be superior to standard-dose vaccine.

DiazGranados et al¹ randomized nearly 32,000 adults age 65 and older to receive either the standard-dose or the high-dose vaccine. The primary end point was laboratory-confirmed influenza caused by any influenza viral type or subtype, in association with a protocol-defined influenzalike illness.

The primary end point was reached in 1.4% of those with the high-dose vaccine and 1.9% of those with the standard-dose vaccine (relative efficacy 24.2%, 95% confidence interval 9.7–36.5). There was also a 26% reduction in respiratory illness regardless of laboratory confirmation. Mortality rates were identical and low (0.5%) in both groups. In those without laboratory confirmation of respiratory illness, there was a 26% lower rate of pneumonia but no statistical difference in rates of hospitalization, medication use, routine office visits, and emergency department visits.

These results can be interpreted as meaning that the high-dose vaccine prevented about a quarter of the laboratory-confirmed influenza cases that would have occurred with the standard-dose vaccine. However, due to the low rate of disease in those given the standard-dose vaccine, the number needed to treat to prevent one influenza infection was about 200 with the high-dose vs the standard-dose vaccine; to prevent one case of pneumonia, more than 270 would need to be treated.

The current price differential as well as the high number needed to treat to prevent one infection may discourage the use of the high-dose vaccine. Medicare Part B pays for one dose of either influenza vaccine per season. For patients who paid out of pocket, the 2014–2015 season cost at a typical pharmacy was about $32 for the standard-dose vaccine and $55 for the high-dose.

PNEUMOCOCCAL VACCINATION

Conjugate vaccine now recommended for seniors

The 23-valent polysaccharide vaccine (Pneumovax) has been available since 1983 and is recommended in the United States for all adults age 65 and over. A 13-valent pneumococcal diphtheria conjugate vaccine (Prevnar 13) has been available since 2010. Until recently, the conjugate vaccine was recommended for children; the only adults for whom it was recommended were those age 19 and over who either were immunocompromised or had a cochlear implant, asplenia, a cerebral spinal fluid leak, or renal failure.

The CAPITA trial² (Community-Acquired Pneumonia Immunisation Trial in Adults) randomized nearly 85,000 people (most 65 and older, and some children) in the Netherlands to receive either the conjugate vaccine or placebo. It found a 46% reduction in community-acquired pneumonia (P = .0006), a 45% reduction in nonbacteremic nonvaccine-type community-acquired pneumonia (P = .0067), and a 75% reduction in vaccine-type invasive pneumococcal disease (P = .0005). Common side effects included pain, swelling at the injection site, limitation of arm movement, fatigue, headache, decreased appetite, chills, and rash.

Based on this one study, the Advisory Committee on Immunization Practices³ recommended that all adults 65 and older receive the conjugate vaccine.

The recommendations for the conjugate vaccine for all ages are complicated. Limited to those age 65 and older, current recommendations are:

• For those who have already received the polysaccharide vaccine: get the conjugated vaccine at least 1 year later
• For those who have never received the polysaccharide vaccine: get the conjugate vaccine now, then the polysaccharide vaccine 6 to 12 months later.

Number needed to treat with the high-dose vs the standard-dose vaccine to prevent one case of
influenza: 200

Whether the Netherlands findings fully apply to the United States is under question. At the time of the study, Dutch infants but not adults had received pneumonia conjugate vaccinations since 2002 with a high compliance rate. Unlike in the United States, the polysaccharide pneumococcal vaccine had not been routinely recommended in the Netherlands. There may have been some indirect immunity due to the “herd” effect, but no direct immunity. With a likely higher background immunity to pneumonia in the United States, the dramatic reduction in infection noted in the Netherlands may not be duplicated here.

For those without Medicare coverage, the 2014–2015 winter season cost at a pharmacy was about $95 for the polysaccharide vaccine and about $200 for the conjugate vaccine. As of February 2, 2015, the Centers for Medicare and Medicaid Services are implementing Medicare Part B coverage to allow initial pneumococcal vaccine for Medicare patients who never received a pneumococcal vaccine under Medicare Part B, and then a different, second pneumococcal vaccine, 1 year after the first vaccine was administered.

HEART FAILURE

Eplerenone’s new role in mild heart failure

Aldosterone antagonists have been recommended for moderate to severe heart failure (New York Heart Association [NYHA] classes III and IV) for some time. The 2013 American College of Cardiology/American Heart Association  (ACC/AHA) guidelines also recommend them for mild heart failure (NYHA II).⁴

The EMPHASIS trial⁵ (Eplerenone in Patients With Systolic Heart Failure and Mild Symptoms) randomized 2,737 patients, median age 69, with NYHA class II heart failure and an ejection fraction of no more than 35% to receive the aldosterone antagonist eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. The trial was stopped early, after a median follow-up of 21 months, when the treatment group was found to have a significantly lower risk of cardiovascular death or hospitalization for heart failure or for any cause.

Of note: hyperkalemia occurred in 11.8% of the eplerenone group vs 7.2% in the placebo group (P < .001). The high frequency of hyperkalemia in the placebo group may have been due to concomitant use of angiotensin-converting enzyme (ACE) inhibitors.

Sodium restriction reasonable

Although sodium restriction has been standard practice in heart failure for decades, restricting sodium in the elderly was given only a IIa (“reasonable”) classification, based on level C (very limited) evidence.⁴

2013 ACC/AHA guidelines recommend aldosterone antagonism for mild heart failure

Strong evidence exists that middle-aged and young older adults with heart failure (with preserved or reduced ejection fraction) should reduce their sodium intake by about 1 g per day or aim for a mean 24-hour urinary sodium excretion of about 2.3 g per day. However, little evidence exists to support a specific long-term target intake, and no evidence exists for “old-old” patients (loosely defined as older than 75 or 80).

Caution with digoxin

Use of digoxin has been recommended in patients with heart failure with reduced ejection fraction to reduce hospitalizations,⁴ but more recent publications have raised questions regarding its safety and efficacy.

Freeman et al,⁶ in a prospective study, followed 2,891 patients with newly diagnosed systolic heart failure over 2.5 years, of whom 529 were prescribed digoxin. The digoxin group had a higher rate of death (14.2 vs 11.2 per 100 patient-years) and heart failure-related hospitalization (28.2 vs 24.4 per 100 person-years).

The study was unable to determine if the digoxin level influenced the results, since about 30% of patients had no digoxin level drawn, and an additional 27% had only one level drawn during the study. For those with measured blood levels, the mean digoxin level for men was 0.83 ng/mL and 1.12 ng/mL for women. Risks and benefits of this medication should be weighed carefully.

Simultaneous interventions beneficial

The following evidence-based interventions are recommended for patients with heart failure with reduced ejection fraction:

• Heart failure education
• A beta-blocker
• An ACE inhibitor
• An aldosterone antagonist for NYHA class II–IV symptoms
• Anticoagulation for atrial fibrillation in patients with added risks (eg, hypertension, diabetes, prior transient ischemic attack or cerebrovascular accident, age at least 75)
• An implantable cardioverter-defibrillator and cardiac resynchronization therapy for select patients with symptoms, increased QRS duration, and left bundle branch block.

Fonarow et al⁷ studied these interventions in an analysis of a prospective study of outpatients with diagnosed heart failure or myocardial infarction and reduced left ventricular ejection fraction. Their nested case-control study compared 1,376 patients, mean age 72, who had died within 24 months and 2,752 propensity-matched controls who survived to 24 months. The survival rate was 37% higher with two simultaneous interventions than with one, and 70% higher with four simultaneous interventions than with one. Benefits plateaued with four to five interventions.

LIPID-LOWERING THERAPY FOR SENIORS

The 2013 ACC/AHA cholesterol guideline⁸ included new recommendations specifically relevant to the elderly. It advocates using a new cardiovascular disease risk calculator that provides an estimate of 10-year risk of atherosclerotic cardiovascular disease (ASCVD), based on data from multiple community-based populations and applicable to African American and non-Hispanic white men and women ages 40 through 79. Primary prevention with a statin is encouraged for those with a 10-year risk of 7.5% or higher. The tool generated controversy from the moment it was announced and may overestimate ASCVD risk by 67% in women and 86% in men.⁹

Emphasis on tolerability

The guideline focuses on statins as the main treatment and de-emphasizes the adjunctive use of other drugs to further lower lipids such as niacin, ezetimibe, and fenofibrate.

Statin tolerability is now stressed rather than specific lipid level targets. The guideline recommends reassessing statin choice and intensity according to pain, tenderness, stiffness, cramping, weakness, and fatigue (class IIa recommendation [“reasonable”], level of evidence B [“limited”]). Also recommended is reassessment of statin choice and intensity for patients older than 75 or for those taking multiple medications, drugs that alter metabolism, and conditions requiring complex medications (class IIa, level of evidence C [“very limited”]). For patients with confusion, statin and nonstatin causes should be considered as the source of the problem (class IIb [“consider”], level of evidence C).

Initiating high-intensity statin therapy is not recommended after age 75. However, continuing such treatment is reasonable for patients already receiving and tolerating the therapy for an appropriate indication. Initiation of moderate-intensity statin therapy in this age group is recommended for those with either clinical atherosclerotic cardiovascular disease or a low-density lipoprotein cholesterol (LDL-C) level of at least 190 mg/dL.

Statin tolerability is now stressed rather than specific lipid level targets

No specific guidance is provided for patients older than age 75 without ASCVD, with LDL-C less than 190 mg/dL, or with diabetes. In these groups, statin therapy may be initiated, continued, or intensified (class IIb, level of evidence C).

HYPERTENSION: LESS AGGRESSIVE GOALS FOR ELDERLY

The eighth Joint National Committee (JNC 8)¹⁰ made nine recommendations for managing high blood pressure, only one of which specifically addresses people 60 and older.

Drug therapy should be initiated if the blood pressure is 150/90 mm Hg or higher, and the blood pressure should be treated to less than that level (grade A recommendation, ie, strong). If treated systolic blood pressure is less than 140 mm Hg without adverse effects, it should be sustained (grade E recommendation, ie, based on expert opinion).

Tension between guidelines

The higher threshold for hypertension treatment and the lower threshold for statin therapy create tension between guidelines, and between guidelines and epidemiologic data.

For example, in a 67-year-old woman without diabetes and with a favorable lipid profile (eg, total cholesterol 130 mg/dL, high-density lipoprotein cholesterol 55 mg/dL), the ACC/AHA ASCVD risk calculator predicts a 10-year risk of less than 7.5% if her systolic blood pressure is 147 mm Hg. If the patient’s blood pressure were 148 or 149 mm Hg and all the other variables were the same, the JNC 8 would not recommend treatment with antihypertensive medication, but the ACC/AHA guidelines would recommend preventive statin therapy.

Another example is the relationship between heart failure and antihypertensive drugs. Multiple studies^11,12 demonstrate a reduction in heart failure incidence with hypertension treatment. A 70-year-old man whose systolic blood pressure is 140 mm Hg has about a 15% lifetime risk of heart failure. If his systolic pressure were 160 mm Hg, his lifetime heart failure risk would be more than 50%.¹³ If his systolic pressure were 149, his lifetime risk of heart failure would be between 15% and 50%, but the JNC 8 criteria do not recommend antihypertensive therapy.

EXERCISE SLOWS PROGRESSION TO FRAILTY

In the absence of a gold standard, frailty has been operationally defined as meeting three out of five phenotypic criteria: diminished grip strength, low energy, slow gait, low physical activity, and unintentional weight loss. A “prefrail” stage, in which one or two criteria are present, identifies a vulnerable subset at high risk of progression to frailty.

About 42% of older adults in the community are considered vulnerable, or prefrail, and about 11% are frail.¹⁴ Interventions at the prefrail stage may prevent progression to frailty, but it is rare, without intervention, for a person to re-achieve the stronger stage once diagnosed with frailty.

Pahor et al¹⁵ randomized 1,635 sedentary adults ages 70 to 89 who met the criteria of prefrailty to either a moderate-intensity exercise program (consisting of aerobic, resistance, and flexibility exercises for 150 minutes per week, performed in a center and at home) or to a health education program with workshops on topics relevant to older adults and upper-extremity stretching exercises. Adherence to the exercise program was verified by questionnaire and an accelerometer device. Participants were assessed every 6 months for an average of 2.6 years.

The primary outcome measure was the development of major mobility disability as defined by the loss of ability to walk 400 m without assistance (a cane was acceptable, but not a walker). The primary outcome occurred in 30.1% of those in the exercise group and 35.5% of the health education group (hazard ratio 0.82, P = .03). Those in the exercise group also had one third fewer falls. No differences were found in death rates. The number needed to treat was about 19 to prevent one person from developing major disability. Those most likely to benefit were those who walked slowly at baseline (< 1.8 mph), were more mobility-impaired, and were more cognitively healthy.

SLOWING DEMENTIA IS STILL AN ELUSIVE GOAL

Vitamin E modestly improves cognitive function but may have a cost

Before new information emerged in 2014 regarding vitamin E and dementia, the best data were from a 1997 study¹⁶ that randomized patients with moderate dementia to either daily vitamin E 2,000 IU, the monoamine oxidase inhibitor selegiline 10 mg, both, or placebo for 2 years. No benefit of treatment for cognitive function was found. However, after adjusting for the baseline Mini-Mental State Examination score, the investigators found that either treatment was associated with a delay of about 7 months in the primary outcome (death, institutionalization, loss of activities of daily living, or severe dementia).

About 42% of community-dwelling older adults are considered ‘prefrail,’ and 11% are frail

Unfortunately, selegiline is often poorly tolerated, causing dyskinesia in more than 10% of patients, nausea in 20%, and confusion, hallucinations, and syncope. Although vitamin E is better tolerated, in high doses it can cause fatigue, headache, and bleeding, with increased risk of hemorrhagic stroke. Studies conflict as to whether it increases the risk of death from any cause.^17,18

Dysken et al,¹⁹ in a study reported in 2014, randomized 613 patients with mild to moderate Alzheimer disease, all of whom were taking an acetylcholinesterase inhibitor, to either daily vitamin E 2,000 IU, memantine 20 mg, both, or placebo. The primary outcome measure was an activities of daily living score (0–78, higher being better), which included the ability to perform such tasks as dressing oneself. Each task was scored from 0 (totally dependent on help) to 4 (able to perform completely independently).

Scores fell in both groups over the mean 2.7 years of the study, but the decrease was slightly slower in the vitamin E group: 3 points less at the end of the study compared with placebo. The groups taking memantine, vitamin E, or both did not differ significantly from one another. No significant differences were found in the secondary outcome of cognitive, neuropsychiatric, functional, and caregiver measures.

Based on the 1997 study, vitamin E may defer the time to important clinical outcomes by 7.5 months over a 2-year period in patients with moderate dementia. Based on the 2014 study, vitamin E may preserve half an activity of daily living over 2.7 years in patients with mild to moderate dementia. On the other hand, high doses of vitamin E may increase the risk of bleeding and falling, and whether they increase the risk of death is unclear.

Antidepressants for behavior issues

Other common problems in patients with major neurocognitive disorders include disturbed perception, thought content, mood, and behavior, collectively called behavioral and psychological symptoms of dementia. No known nondrug intervention is consistently effective for these problems, and no drug approved by the US Food and Drug Administration (FDA), except for a fixed-dose combination of dextromethorphan and quinidine, addresses any specific symptom.

Porsteinsson et al²⁰ randomized 186 patients with Alzheimer disease and agitation to a psychological intervention plus either the selective serotonin reuptake inhibitor citalopram (titrated from 10 to 30 mg per day based on response and tolerability) or placebo. Agitation was reduced with citalopram compared with placebo, based on the agitation subscale of the Neurobehavioral Rating Scale.

Of those taking citalopram, 40% were much or very much improved, compared with 26% of those taking placebo. These results are comparable to or better than those with antipsychotic drugs, which should be avoided for treating dementia-related psychosis in elderly patients because of black-box warnings.

No differences were found in activities of daily living. An interesting finding, not seen in other studies, is that the Mini-Mental Status Examination score declined by 1 point in the treatment group vs no change in the placebo group (P = .03).

Although vitamin E may delay important outcomes in dementia, high doses may increase the risk of bleeding and falling

Prolonged QTc was found in 12.5% in the citalopram group vs 4.3% in the placebo group (P = .01). The FDA issued a warning in 2012 of a dose-dependent effect of citalopram on QTc and recommended a maximum dose of 20 mg for those over age 60; for “poor metabolizers” of cytochrome P450 2C19 (CYP 2C19); and for those taking medications that inhibit CYP 2C19, including proton pump inhibitors, cimetidine, fluvoxamine, fluoxetine, indomethacin, ketoconazole, modafinil, and probenecid. The United Kingdom has extended this warning to escitalopram. Unfortunately, in the Porsteinsson study, nearly 80% of the treatment group received the 30-mg dose and only 15% received the 20-mg dose, which provided insufficient data for independent analysis.

Possibly, citalopram cannot be administered in a dosage sufficient to produce the benefits seen in the study. Using escitalopram may also be risky. Based on this study, it would be prudent to monitor QTc when using these drugs.

Dextromethorphan and quinidine

A fixed-dose combination of dextromethorphan and quinidine (Nuedexta) was recently approved by the FDA for treatment of pseudobulbar affect in individuals with stroke, traumatic brain injury, or dementia. Pseudobulbar affect has been defined as a condition of contextually inappropriate or exaggerated emotional expression that often occurs in adults with neurologic damage.

Using a 20/10-mg dose combination, a small 12-week noncomparative trial demonstrated measurable improvement in pseudobulbar symptoms after 30 days (as measured by the Center for Neurologic Study-Lability Scale).²¹ Though individuals enrolled in this trial appeared to tolerate this dose, additional trials still need to be conducted to more clearly determine its long-term safety and efficacy. It is not approved for dementia with agitation, but a phase 2 trial suggests a benefit compared with placebo in reducing agitation and caregiver burden.²²

RISKS OF MILD COGNITIVE IMPAIRMENT

The spectrum of cognitive impairment ranges from mild cognitive impairment (MCI), in which deficits are evident on neuropsychological testing but the person maintains overall function, to the different stages of dementia (mild, moderate, and severe). MCI was documented in the Cardiovascular Health Study in 22% of adults 75 and older.²³

Despite presenting with apparently normal function, elderly people with MCI have a higher risk of falls, rehospitalization, and delirium. Screening is not typically performed for MCI in primary care. No study has compared clinical outcomes after screening vs not screening for cognitive impairment (whether MCI or dementia), and the US Preventive Services Task Force maintains that there is insufficient evidence for screening.²⁴

Unrecognized cognitive impairment affects discharge outcomes

Nazir et al,²⁵ in a 1-year longitudinal study, compared 976 patients age 65 and older who upon admission to a public hospital were either diagnosed with cognitive impairment (defined as scoring 7 or less on the 10-question Short Portable Mental Status Questionnaire) or not. They found that 42.5% were cognitively impaired on admission. Overall, 36.5% of patients were discharged to a facility rather than home; those who were cognitively impaired, older, and sicker were more likely to be discharged to a facility.

The elderly population is heterogeneous

Interestingly, among those discharged to a facility, patients with cognitive impairment were less likely to be subsequently rehospitalized or die within 30 days of hospital discharge than those without cognitive impairment. Whether this can be explained by differences in comorbidities between the groups was not explored. Those discharged home had similar rates of death and rehospitalization whether or not they were cognitively impaired.

Patel et al²⁶ screened 720 older patients upon discharge after hospitalization for heart failure with the Mini-Cog (a 3-minute test that consists of recall of three words and the ability to draw a clock face). About a quarter of patients were diagnosed with cognitive impairment based on this test.

Among those discharged home (about two-thirds of the group overall), patients were much more likely to be rehospitalized or die within 30 days if they were cognitively impaired. Among those discharged to a facility, the rates between the two groups were similar for the first 20 days; after that, people in the cognitively impaired group were much more likely to die or be readmitted to a hospital.

Dodson et al,²⁷ in a study of 282 hospitalized patients with heart failure (mean age 80), identified 47% as having cognitive impairment at the time of hospitalization based on a score of less than 25 on the Mini-Mental State Examination. Of those found to have mild cognitive impairment (score 21–24), only 11% had documentation of a cognitive deficit in the medical record, and 39% of those found to have moderate to severe cognitive impairment (score < 21) had documentation of it in the medical record. Those with unrecognized impairment were 1.5 times more likely to die or be rehospitalized within 6 months than those with documented impairment.

Do interventions help?

It is unclear whether developing specific interventions tailored to cognitive impairment improves outcomes.

Davis et al²⁸ studied 125 patients hospitalized for heart failure who were identified as having mild cognitive impairment based on a Montreal Cognitive Assessment score of 17 to 25 (out of 30) points. Patients were randomly assigned to either a targeted self-care teaching intervention or usual discharge care. The intervention included education and customized instruction on self-care tasks such as managing symptoms, organizing medications, and measuring fluid and sodium intake.

Thirty days after discharge, the intervention group had greater knowledge about heart failure than the control group, but no significant difference was found in ability to care for themselves or in readmission rates.

Interventions that target the patient-caregiver dyad may have more success. A pilot project in Indiana²⁹ that developed an integrative care model for older people with mild cognitive impairment, dementia, or depression that targeted patients as well as their caregivers found that compared with patients from area primary care clinics, their patients had lower rehospitalization rates within 30 days of discharge (11% vs 20%) and higher rates of achieving a hemoglobin A_1c of less than 8% (78% vs 51%). Results of an expanded innovations demonstration project awarded by the Centers for Medicare and Medicaid Services are pending.

The following more recently published data show promise for prevention of dementia through nonpharmacologic interventions.

The FINGER trial³⁰ (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) screened 2,654 Finnish individuals ages 60 to 77 using the Cardiovascular Risk Factors, Aging and Dementia risk tool, identifying 1,260 individuals with higher levels of cognitive impairment and randomizing them to a 2-year intervention consisting of exercise, cognitive training, and vascular risk monitoring (n = 631), or a control group provided with general health advice only (n = 629). Neuropsychological testing was conducted to measure differences between the groups, and at the end of the study, the mean Z-score difference in the total testing score between the intervention and control group was 0.22 (P = .30). This trial demonstrated that if cognitive impairment were identified, a multimodal intervention could improve or maintain cognitive function in at-risk elderly individuals.