Drug Therapy

More than 30 years into the human immunodeficiency virus (HIV) epidemic, our understanding of the needs of women living with this virus continues to evolve. In the early years of the epidemic, managing HIV was all about preventing death and treating opportunistic infections. But now it is also about enabling patients to live long, healthy, and productive lives and preventing new HIV infections. In women, these goals can only be achieved by paying careful attention to sex-specific issues.

See related editorial

As a result of longer survival, HIV-infected persons are increasingly developing common health problems that also affect the general population and that require screening, management, and monitoring by primary care providers. Because people infected with HIV are typically seen by both an HIV specialist and a primary care provider, HIV specialists need to be familiar with primary care issues and primary care providers need to be familiar with HIV care recommendations in order to provide optimal care.

AFRICAN AMERICAN WOMEN BEAR A DISPROPORTIONATE BURDEN

In the United States, HIV was first reported in women in 1983 among those who had been steady sexual partners of males with acquired immune deficiency syndrome.¹ Although men with HIV still outnumber women, the number of women with HIV has increased rapidly. At the end of 2010 an estimated one in four people with HIV in the United States was female.²

African American women bear a disproportionate burden of the disease (Table 1).³ In 2010, women accounted for an estimated 9,500 (20%) of the approximately 45,000 new infections occurring in the United States. Of these newly infected women, 64% were black, 18% were white, and 15% were Hispanic. Yet blacks make up only about 12% of the US population, whites make up 68%, and Hispanics 14%.

Regardless of race or ethnicity, unprotected heterosexual contact is the most common mode of transmission of HIV in women.²

Although the overall rates of HIV infection in the United States are relatively low, certain areas of the country have rates similar to those in sub-Saharan Africa, where most HIV-infected people reside.⁴ The HIV Prevention Trials Network found that the incidence of HIV infection in US women living in these “hot spots,” with high rates of poverty and HIV, was 0.32% per year. Compare this with the 2009 estimate of HIV incidence in the general population of US black women of similar age (0.05% per year) and the adult incidence rates in Congo (0.28% per year) and Kenya (0.53% per year).⁵ To better understand the epidemiology of HIV infection in women and concentrate our prevention efforts, we need to focus on these hot spots.

Misinformation abounds in these hot spots, as does disease. In a survey of residents of the South Side Chicago Housing Authority facilities,⁶ many were aware that effective antiretroviral therapy existed, but one-fourth thought that there was an effective HIV vaccine, and 13% thought there was a cure.

In the early years, an HIV diagnosis was essentially a death sentence. Samji et al⁷ estimated that life expectancy of patients who were prescribed antiretroviral therapy in the United States and Canada increased from 36.1 years in 2000–2002 to 51.4 years in 2006–2007, with the greatest increases in those who started with a baseline CD4 count above 350 cells/mm³. Now, a 20-year-old HIV-positive person with a CD4 count greater than 350 cells/mm³ can expect to live into his or her early 70s.

But not all patients achieve these benefits. In 2009, despite major advances in diagnosis and treatment, HIV was the fourth leading cause of death among African American women ages 25 to 44, causing about 800 deaths, or 9% of all deaths in this group.⁸

TEST ALL, UNLESS THEY OPT OUT

Testing is vital in efforts to prevent and treat HIV infection. In 2006, the US Centers for Disease Control and Prevention (CDC) recommended that everyone between the ages of 13 and 64 be screened for HIV regardless of risk.⁹

The CDC recommends an opt-out strategy.⁹ Rather than ask a patient whether he or she wants to be tested for HIV, the provider says something like, “I advise all of my patients to have an HIV test; as long as you have no objection, we will send you to the lab to have it done.” This approach reduces barriers to HIV testing by eliminating pretest counseling and by making HIV testing routine and the standard of care. Separate consent is not required—clinicians just need to document whether the patient has accepted or declined the test.

Testing should be offered at least once and can be done in any health care setting, including primary care offices and clinics, emergency rooms, health departments, and urgent care centers.⁹ Patients at higher risk (injection drug users and their sex partners; people who exchange sex for money or drugs; sex partners of HIV-infected people; men who have sex with men; and heterosexuals who themselves or whose sex partners have had more than one sex partner since their most recent HIV test) should receive repeat screening annually.

HIV testing should also be offered to all pregnant women at entry into care and again in the third trimester. This strategy is cost-effective even in areas of low prevalence.⁹ Since 2006, other professional organizations have made HIV testing recommendations as well (Table 2).^9–12

A cost-effectiveness analysis suggested that routine opt-out testing is economically justified if the prevalence of HIV is greater than 0.2%.¹³

HIV-POSITIVE WOMEN NEED ROUTINE GYNECOLOGIC CARE

It is important for women with HIV to receive routine gynecologic care. Women with HIV have gynecologic problems similar to those of all women; however, they may be more vulnerable to certain conditions such as human papillomavirus (HPV) infection, which may be related to HIV disease or associated immunosuppression. In addition, pregnancy and family planning pose special challenges in this group.¹⁴

Cervical cancer screening

Effective screening and timely treatment of precancerous cervical lesions are key in preventing cervical cancer in women with or without HIV.

Persistent infection with HPV is necessary for the development of precancerous lesions as well as invasive cervical cancer. Most new cases of HPV infection in the general population resolve spontaneously within 2 years. However, in HIV-infected women, HPV infection is more likely to persist and progress to precancerous lesions of the cervix. This association is strongest in women with more compromised immune function as reflected by low CD4 cell counts and high viral loads.¹⁴ Women with HIV have higher rates of infection with high-risk HPV strains and of cervical intraepithelial neoplasia compared with their HIV-negative counterparts.¹⁴ The incidence of cervical cancer is five to six times higher in HIV-infected women in the United States than in the general population.¹⁵

According to guidelines from the Infectious Diseases Society of America,¹⁶ the American College of Obstetricians and Gynecologists,¹⁰ the CDC,¹⁷ and the American Cancer Society,¹⁸ all HIV-infected women should undergo cervical Papanicolaou (Pap) screening upon initiation into care, and this test should be repeated at 6 months and then annually if the results are normal. Patients with abnormalities on the Pap test should undergo colposcopy and, possibly, also biopsy. These abnormalities include atypical squamous cells of unknown significance and higher-grade lesions.¹⁶

Nearly one-fourth of HIV-positive women do not receive annual Pap smears despite engagement in care.¹⁹ This is unacceptable, because half of the cases of cervical cancer diagnosed in the United States are in women who never received appropriate screening, and an additional 10% are in women who have not been screened in the previous 5 years.¹⁹

In HIV-infected women who have had a total hysterectomy, whether to continue Pap testing depends on their history before the surgery. Continued vaginal Pap smear screening is recommended after hysterectomy (including removal of the cervix) in HIV-infected women who have a history of cervical intraepithelial neoplasia grades 2 or 3 or invasive cancer.^10,17,20

TREATING HIV IN WOMEN: SPECIAL CONSIDERATIONS

Because it is not yet possible to eradicate the HIV virus, the goals of antiretroviral therapy are to reduce HIV-associated morbidity and mortality, to restore and preserve immune function, to suppress viral load, and to prevent sexual and, in women, perinatal transmission of the virus.²¹

Antiretroviral therapy is recommended for all HIV-infected patients regardless of the CD4 count, although the strength of recommendation is weaker with higher CD4 counts (Table  3).²¹ The recommendations for starting antiretroviral therapy and the goals of treatment are the same for men and women. Table 4 summarizes the recommendations for adolescents and adults who are new to treatment.²¹ For women, additional factors that should be taken into account when considering a regimen include pregnancy potential and whether the drugs chosen for the regimen are considered safe in pregnancy.

Since the early years of the HIV epidemic, researchers have debated whether women attain the same benefits from antiretroviral therapy as men. US Food and Drug Administration investigators performed a meta-analysis of the efficacy outcomes in women in studies of antiretroviral drugs published between 2000 and 2008. They included randomized clinical trials reporting at least 48-week efficacy outcomes, with viral suppression defined as HIV RNA less than 50 copies/mL. The combined database included 40 trials of 16 drugs from 7 drug classes with a total of 20,328 HIV-positive participants. Overall, there were no clinically or statistically significant differences between the sexes in 48-week efficacy outcomes or in rates of trial discontinuation due to adverse events, loss to follow-up, or death.²²

Antiretroviral therapy may, however, cause different adverse effects in women than in men. For example:

Nevirapine, a nonnucleoside reverse transcriptase inhibitor, has been associated with the development of a rash and potentially life-threatening hepatotoxicity, more commonly in women than in men and at lower CD4 counts in women. This resulted in recommendations²¹ to avoid starting a nevirapine-containing regimen in women with CD4 counts greater than 250 cells/mm³ and in men with CD4 counts greater than 400 cells/mm³.

Ritonavir has been observed to cause a higher incidence of nausea and vomiting in women and a higher incidence of diarrhea in men. These are thought to be due to differences between men and women in weight and pharmacokinetics.²³

PRECONCEPTION COUNSELING FOR HIV-POSITIVE WOMEN

Preconception counseling is an essential component of both primary and preventive care and should be considered the standard of care for all women of reproductive age who have HIV.²⁴ Health care providers who fully understand the impact of HIV infection and associated comorbidities upon a woman’s reproductive health, fertility desires, and family planning needs are better prepared to assist in their patients’ reproductive health decisions.

The first few weeks of pregnancy are the most critical period in fetal development. During this time, a woman should be healthy and avoid any activities or substances that could cause adverse maternal or fetal outcomes. However, most patients present for prenatal care after this critical time period—thus the need for preconception counseling. Both the Infectious Diseases Society of America and the HIV Medicine Association recommend that all HIV-infected women of childbearing age be asked about their pregnancy plans and desires at the start of care and routinely thereafter.¹⁶

The goals of preconception care in women with HIV are to prevent unintended pregnancy, optimize maternal health before pregnancy, optimize pregnancy outcomes for mother and fetus, prevent perinatal HIV transmission, and prevent HIV transmission to an HIV-negative partner when trying to conceive.²⁴

Goal 1: Prevent unintended pregnancy

Nearly half of all pregnancies in the United States are unintended.²⁵ Moreover, the Women’s Interagency HIV Study²⁶ showed that women with HIV are underusing effective contraception. In the Medical Monitoring Project, 85% of the women who had been pregnant since being diagnosed with HIV said that at least one pregnancy was unplanned.²⁷

The consequences of unintended and unplanned pregnancies are serious and add significant burden to women, men, and families. Women who do not wish to become pregnant should be advised to use an effective method of contraception.

Contraception

Contraception use varies worldwide. Factors affecting its use include the methods available, patient choice, current health conditions, religious beliefs, perception of method effectiveness, and side effects.²⁴

The Women’s Interagency HIV Study evaluated trends in contraception use from 1998 to 2010. Condoms were the most common form of contraception, and their use changed little over time. Fewer than 15% of women with HIV used no contraception. The use of long-acting reversible contraception, including injectable progestins, implants, and intrauterine devices, which minimize the need for user adherence, increased among HIV-negative women but not among HIV-positive women.²⁸

The World Health Organization states that all available methods are safe for women with HIV except for spermicides with or without a diaphragm, as there is evidence linking the use of spermicides to an increased risk of HIV transmission (Table 5).²⁹

Some antiretroviral drugs may reduce the effectiveness of some contraceptives (Table 6); however, recommendations are based on pharmacokinetic studies, not on outcome studies. Condoms should be recommended not only to protect against pregnancy, but also to protect against sexually transmitted infections.

Goal 2: Optimize maternal health before pregnancy

Maternal health should be optimized before conceiving to reduce the risk of pregnancy-related morbidities and poor birth outcomes. This includes screening for other infections and ensuring that other comorbidities, such as hypertension, diabetes, substance abuse, and mental illness, are well managed with medications that are safe to use in pregnancy (Table 7).

Goal 3: Prevent perinatal HIV transmission

Educating the patient about perinatal transmission is a fundamental component of preconception counseling. Topics that need to be addressed are transmission risk and methods to reduce the risk, including not breastfeeding after delivery.

Goal 4: Prevent HIV transmission to an uninfected partner when trying to conceive

HIV-discordant couples who desire pregnancy should receive appropriate counseling about methods to minimize risk of transmission to the uninfected partner while trying to conceive. There are a number of effective methods and techniques, which are beyond the scope of this review. Key components of all methods are to screen for and treat sexually transmitted infections in both partners and to use effective antiretroviral therapy and attain maximal viral suppression in the HIV-positive partner.

Antiretroviral therapy for the HIV-infected partner significantly reduced the risk of HIV transmission by 96% in the HIV Prevention Trials Network 052 trial.³⁰ Of note: this reduction was the result of both risk-reduction counseling and antiretroviral therapy. This was the first randomized clinical trial to demonstrate that antiretroviral therapy in those with some preserved immune function (CD4 counts 350–500 cells/mm³) in conjunction with risk-reduction counseling can reduce HIV transmission to an uninfected partner.

Vaginal insemination without intercourse is another option for female-positive couples. The man ejaculates into a condom without spermicide, and the contents are introduced with a non-needle syringe or turkey baster. This can be done at home and confers no risk to the uninfected male partner.³¹ Chances of pregnancy can be maximized by insemination during the most fertile days of the menstrual cycle.

Preexposure prophylaxis combined with timed intercourse. In a study in Switzerland, the infected male partner was given antiretroviral therapy to suppress his viral load to less than 50 copies/mL for at least 6 months, and luteinizing hormone was measured every day in the urine of the noninfected female partner. When the urinary luteinizing hormone level reached a peak, the woman received a dose of tenofovir in the morning, the couple had unprotected intercourse, and the woman took a second dose the next morning. In 53 cases, none of the female partners seroconverted for HIV.³²

Health care providers need to document and update the relationship status, partner HIV status, and fertility desires of their HIV patients, both men and women, on a regular basis. Patient education should include awareness of referrals and options to help safely conceive when desired and achieve effective contraception when not.³³

WHEN HIV-POSITIVE WOMEN BECOME PREGNANT

Screening for HIV during pregnancy

The CDC recommends prenatal screening for HIV in the first trimester or at entry into prenatal care. A repeat HIV test should be offered in the third trimester for women at risk of acquiring HIV, for women who have signs or symptoms of early HIV infection, in health care settings where prenatal testing yields at least 1 case of HIV infection per 1,000 women screened, and in areas of high HIV incidence. If women present to labor and delivery with unknown HIV status, rapid HIV testing should be done.⁹

If a woman acquires HIV during pregnancy, the infection may not be detected and may be transmitted to the infant at birth. From 2002 to 2006 in New York State, 3,396 HIV-exposed babies were born. Of these, 9 (22%) of 41 infants born to mothers who acquired HIV during pregnancy became infected, compared with 1.8% of those born to mothers who acquired HIV before pregnancy. Maternal acquisition of HIV during pregnancy was documented in only 1.3% of perinatal HIV exposures, but it was associated with 9 (13.8%) of the 65 perinatal transmission cases.³⁴

Providers should be aware of the signs and symptoms of acute HIV infection and should have a low threshold for repeating HIV testing at any time during pregnancy. It has been estimated that 40% to 90% of patients with acute HIV infection experience fever, lymphadenopathy, pharyngitis, skin rash, myalgia, arthralgia, or other symptoms.³⁵ Providers often do not recognize acute HIV infection, however, because the symptoms are similar to those of other common illnesses. Also, some individuals with the condition have no symptoms.

Antiretroviral therapy during pregnancy

In a landmark study, AIDS Clinical Trial Group 076 demonstrated that zidovudine monotherapy given during pregnancy, labor, and delivery and to the newborn reduced the risk of HIV transmission to the infant by 67%, from 25% to 8%.³⁶ Other studies demonstrated that combination therapy further decreased the risk of HIV transmission to 1% to 2%.³⁷

The US Department of Health and Human Services recommends that all HIV-positive women who are pregnant receive effective combination antiretroviral therapy regardless of CD4 count to minimize the risk of mother-to-child transmission.³⁷

The goals of HIV treatment during pregnancy are to maintain the woman’s health, restore her immune system, suppress viral replication, and decrease the risk of perinatal transmission. The preferred antiretroviral therapy for pregnant women differs from that for nonpregnant women and is based on evolving experience and information about safety, efficacy, and tolerability in pregnancy (Table 8). A woman who presents for prenatal care on a suppressive regimen should continue that regimen as long as she can tolerate it because there is a risk of losing virologic control when switching regimens, and this may increase the risk of perinatal transmission.³⁷

Physiologic changes that occur during pregnancy may alter drug disposition, which could potentially lead to decreased drug exposure. Some of the changes include an increase in total body water, decreased protein binding, induction of hepatic metabolic pathways, and increased clearance of drugs eliminated by the kidneys.³⁸ These changes may be associated with incomplete virologic suppression, virologic failure, or development of drug resistance, so altered doses of some antiretroviral drugs or careful monitoring of viral load should be considered, particularly in the second and third trimester.

Delivery

Women who have a viral load greater than 1,000 copies/mL near the end of pregnancy should undergo a cesarean delivery at 38 weeks and, before surgery, should receive intravenous zidovudine to reduce the risk of perinatal transmission. For women with viral loads below the threshold of 1,000 copies/mL, there is no proven added benefit to cesarean delivery, and in this situation it should be performed only for standard obstetric indications. Antiretroviral regimens should be continued during labor.³⁷

HIV IN OLDER ADULTS

By 2015, approximately 50% of people with HIV will be over age 50.³⁹ Unfortunately, older people and their providers often underestimate their risk of acquiring HIV. Many older people are newly single and may engage in sexual activity with new partners. Also, older people may be reluctant to use condoms as the need for contraception is past.^40,41

Baseline HIV RNA levels tend to be higher and CD4 cell counts lower in patients diagnosed with HIV at older ages. These observations support previous ones that older HIV-infected patients may have advanced HIV disease at the time of diagnosis, perhaps in part due to delayed testing.⁴² Other possible factors are limited income, comorbid illness, polypharmacy, and insufficient data on drug interactions in the elderly.^41,42

A prompt diagnosis is important for older patients because HIV may accelerate aging, and aging may speed up HIV progression. Studies have shown that aging is associated with more rapid progression to AIDS, particularly among people who are older than 40 at seroconversion.⁴³ Other studies have reported that older patients have better virologic responses to antiretroviral therapy but have a blunted immune response, more AIDS-defining events, and a higher mortality rate than younger patients.⁴²

More than 30 years into the human immunodeficiency virus (HIV) epidemic, our understanding of the needs of women living with this virus continues to evolve. In the early years of the epidemic, managing HIV was all about preventing death and treating opportunistic infections. But now it is also about enabling patients to live long, healthy, and productive lives and preventing new HIV infections. In women, these goals can only be achieved by paying careful attention to sex-specific issues.

See related editorial

As a result of longer survival, HIV-infected persons are increasingly developing common health problems that also affect the general population and that require screening, management, and monitoring by primary care providers. Because people infected with HIV are typically seen by both an HIV specialist and a primary care provider, HIV specialists need to be familiar with primary care issues and primary care providers need to be familiar with HIV care recommendations in order to provide optimal care.

AFRICAN AMERICAN WOMEN BEAR A DISPROPORTIONATE BURDEN

In the United States, HIV was first reported in women in 1983 among those who had been steady sexual partners of males with acquired immune deficiency syndrome.¹ Although men with HIV still outnumber women, the number of women with HIV has increased rapidly. At the end of 2010 an estimated one in four people with HIV in the United States was female.²

African American women bear a disproportionate burden of the disease (Table 1).³ In 2010, women accounted for an estimated 9,500 (20%) of the approximately 45,000 new infections occurring in the United States. Of these newly infected women, 64% were black, 18% were white, and 15% were Hispanic. Yet blacks make up only about 12% of the US population, whites make up 68%, and Hispanics 14%.

Regardless of race or ethnicity, unprotected heterosexual contact is the most common mode of transmission of HIV in women.²

Although the overall rates of HIV infection in the United States are relatively low, certain areas of the country have rates similar to those in sub-Saharan Africa, where most HIV-infected people reside.⁴ The HIV Prevention Trials Network found that the incidence of HIV infection in US women living in these “hot spots,” with high rates of poverty and HIV, was 0.32% per year. Compare this with the 2009 estimate of HIV incidence in the general population of US black women of similar age (0.05% per year) and the adult incidence rates in Congo (0.28% per year) and Kenya (0.53% per year).⁵ To better understand the epidemiology of HIV infection in women and concentrate our prevention efforts, we need to focus on these hot spots.

Misinformation abounds in these hot spots, as does disease. In a survey of residents of the South Side Chicago Housing Authority facilities,⁶ many were aware that effective antiretroviral therapy existed, but one-fourth thought that there was an effective HIV vaccine, and 13% thought there was a cure.

In the early years, an HIV diagnosis was essentially a death sentence. Samji et al⁷ estimated that life expectancy of patients who were prescribed antiretroviral therapy in the United States and Canada increased from 36.1 years in 2000–2002 to 51.4 years in 2006–2007, with the greatest increases in those who started with a baseline CD4 count above 350 cells/mm³. Now, a 20-year-old HIV-positive person with a CD4 count greater than 350 cells/mm³ can expect to live into his or her early 70s.

But not all patients achieve these benefits. In 2009, despite major advances in diagnosis and treatment, HIV was the fourth leading cause of death among African American women ages 25 to 44, causing about 800 deaths, or 9% of all deaths in this group.⁸

TEST ALL, UNLESS THEY OPT OUT

Testing is vital in efforts to prevent and treat HIV infection. In 2006, the US Centers for Disease Control and Prevention (CDC) recommended that everyone between the ages of 13 and 64 be screened for HIV regardless of risk.⁹

The CDC recommends an opt-out strategy.⁹ Rather than ask a patient whether he or she wants to be tested for HIV, the provider says something like, “I advise all of my patients to have an HIV test; as long as you have no objection, we will send you to the lab to have it done.” This approach reduces barriers to HIV testing by eliminating pretest counseling and by making HIV testing routine and the standard of care. Separate consent is not required—clinicians just need to document whether the patient has accepted or declined the test.

Testing should be offered at least once and can be done in any health care setting, including primary care offices and clinics, emergency rooms, health departments, and urgent care centers.⁹ Patients at higher risk (injection drug users and their sex partners; people who exchange sex for money or drugs; sex partners of HIV-infected people; men who have sex with men; and heterosexuals who themselves or whose sex partners have had more than one sex partner since their most recent HIV test) should receive repeat screening annually.

HIV testing should also be offered to all pregnant women at entry into care and again in the third trimester. This strategy is cost-effective even in areas of low prevalence.⁹ Since 2006, other professional organizations have made HIV testing recommendations as well (Table 2).^9–12

A cost-effectiveness analysis suggested that routine opt-out testing is economically justified if the prevalence of HIV is greater than 0.2%.¹³

HIV-POSITIVE WOMEN NEED ROUTINE GYNECOLOGIC CARE

It is important for women with HIV to receive routine gynecologic care. Women with HIV have gynecologic problems similar to those of all women; however, they may be more vulnerable to certain conditions such as human papillomavirus (HPV) infection, which may be related to HIV disease or associated immunosuppression. In addition, pregnancy and family planning pose special challenges in this group.¹⁴

Cervical cancer screening

Effective screening and timely treatment of precancerous cervical lesions are key in preventing cervical cancer in women with or without HIV.

Persistent infection with HPV is necessary for the development of precancerous lesions as well as invasive cervical cancer. Most new cases of HPV infection in the general population resolve spontaneously within 2 years. However, in HIV-infected women, HPV infection is more likely to persist and progress to precancerous lesions of the cervix. This association is strongest in women with more compromised immune function as reflected by low CD4 cell counts and high viral loads.¹⁴ Women with HIV have higher rates of infection with high-risk HPV strains and of cervical intraepithelial neoplasia compared with their HIV-negative counterparts.¹⁴ The incidence of cervical cancer is five to six times higher in HIV-infected women in the United States than in the general population.¹⁵

According to guidelines from the Infectious Diseases Society of America,¹⁶ the American College of Obstetricians and Gynecologists,¹⁰ the CDC,¹⁷ and the American Cancer Society,¹⁸ all HIV-infected women should undergo cervical Papanicolaou (Pap) screening upon initiation into care, and this test should be repeated at 6 months and then annually if the results are normal. Patients with abnormalities on the Pap test should undergo colposcopy and, possibly, also biopsy. These abnormalities include atypical squamous cells of unknown significance and higher-grade lesions.¹⁶

Nearly one-fourth of HIV-positive women do not receive annual Pap smears despite engagement in care.¹⁹ This is unacceptable, because half of the cases of cervical cancer diagnosed in the United States are in women who never received appropriate screening, and an additional 10% are in women who have not been screened in the previous 5 years.¹⁹

In HIV-infected women who have had a total hysterectomy, whether to continue Pap testing depends on their history before the surgery. Continued vaginal Pap smear screening is recommended after hysterectomy (including removal of the cervix) in HIV-infected women who have a history of cervical intraepithelial neoplasia grades 2 or 3 or invasive cancer.^10,17,20

TREATING HIV IN WOMEN: SPECIAL CONSIDERATIONS

Because it is not yet possible to eradicate the HIV virus, the goals of antiretroviral therapy are to reduce HIV-associated morbidity and mortality, to restore and preserve immune function, to suppress viral load, and to prevent sexual and, in women, perinatal transmission of the virus.²¹

Antiretroviral therapy is recommended for all HIV-infected patients regardless of the CD4 count, although the strength of recommendation is weaker with higher CD4 counts (Table  3).²¹ The recommendations for starting antiretroviral therapy and the goals of treatment are the same for men and women. Table 4 summarizes the recommendations for adolescents and adults who are new to treatment.²¹ For women, additional factors that should be taken into account when considering a regimen include pregnancy potential and whether the drugs chosen for the regimen are considered safe in pregnancy.

Since the early years of the HIV epidemic, researchers have debated whether women attain the same benefits from antiretroviral therapy as men. US Food and Drug Administration investigators performed a meta-analysis of the efficacy outcomes in women in studies of antiretroviral drugs published between 2000 and 2008. They included randomized clinical trials reporting at least 48-week efficacy outcomes, with viral suppression defined as HIV RNA less than 50 copies/mL. The combined database included 40 trials of 16 drugs from 7 drug classes with a total of 20,328 HIV-positive participants. Overall, there were no clinically or statistically significant differences between the sexes in 48-week efficacy outcomes or in rates of trial discontinuation due to adverse events, loss to follow-up, or death.²²

Antiretroviral therapy may, however, cause different adverse effects in women than in men. For example:

Nevirapine, a nonnucleoside reverse transcriptase inhibitor, has been associated with the development of a rash and potentially life-threatening hepatotoxicity, more commonly in women than in men and at lower CD4 counts in women. This resulted in recommendations²¹ to avoid starting a nevirapine-containing regimen in women with CD4 counts greater than 250 cells/mm³ and in men with CD4 counts greater than 400 cells/mm³.

Ritonavir has been observed to cause a higher incidence of nausea and vomiting in women and a higher incidence of diarrhea in men. These are thought to be due to differences between men and women in weight and pharmacokinetics.²³

PRECONCEPTION COUNSELING FOR HIV-POSITIVE WOMEN

Preconception counseling is an essential component of both primary and preventive care and should be considered the standard of care for all women of reproductive age who have HIV.²⁴ Health care providers who fully understand the impact of HIV infection and associated comorbidities upon a woman’s reproductive health, fertility desires, and family planning needs are better prepared to assist in their patients’ reproductive health decisions.

The first few weeks of pregnancy are the most critical period in fetal development. During this time, a woman should be healthy and avoid any activities or substances that could cause adverse maternal or fetal outcomes. However, most patients present for prenatal care after this critical time period—thus the need for preconception counseling. Both the Infectious Diseases Society of America and the HIV Medicine Association recommend that all HIV-infected women of childbearing age be asked about their pregnancy plans and desires at the start of care and routinely thereafter.¹⁶

The goals of preconception care in women with HIV are to prevent unintended pregnancy, optimize maternal health before pregnancy, optimize pregnancy outcomes for mother and fetus, prevent perinatal HIV transmission, and prevent HIV transmission to an HIV-negative partner when trying to conceive.²⁴

Goal 1: Prevent unintended pregnancy

Nearly half of all pregnancies in the United States are unintended.²⁵ Moreover, the Women’s Interagency HIV Study²⁶ showed that women with HIV are underusing effective contraception. In the Medical Monitoring Project, 85% of the women who had been pregnant since being diagnosed with HIV said that at least one pregnancy was unplanned.²⁷

The consequences of unintended and unplanned pregnancies are serious and add significant burden to women, men, and families. Women who do not wish to become pregnant should be advised to use an effective method of contraception.

Contraception

Contraception use varies worldwide. Factors affecting its use include the methods available, patient choice, current health conditions, religious beliefs, perception of method effectiveness, and side effects.²⁴

The Women’s Interagency HIV Study evaluated trends in contraception use from 1998 to 2010. Condoms were the most common form of contraception, and their use changed little over time. Fewer than 15% of women with HIV used no contraception. The use of long-acting reversible contraception, including injectable progestins, implants, and intrauterine devices, which minimize the need for user adherence, increased among HIV-negative women but not among HIV-positive women.²⁸

The World Health Organization states that all available methods are safe for women with HIV except for spermicides with or without a diaphragm, as there is evidence linking the use of spermicides to an increased risk of HIV transmission (Table 5).²⁹

Some antiretroviral drugs may reduce the effectiveness of some contraceptives (Table 6); however, recommendations are based on pharmacokinetic studies, not on outcome studies. Condoms should be recommended not only to protect against pregnancy, but also to protect against sexually transmitted infections.

Goal 2: Optimize maternal health before pregnancy

Maternal health should be optimized before conceiving to reduce the risk of pregnancy-related morbidities and poor birth outcomes. This includes screening for other infections and ensuring that other comorbidities, such as hypertension, diabetes, substance abuse, and mental illness, are well managed with medications that are safe to use in pregnancy (Table 7).

Goal 3: Prevent perinatal HIV transmission

Educating the patient about perinatal transmission is a fundamental component of preconception counseling. Topics that need to be addressed are transmission risk and methods to reduce the risk, including not breastfeeding after delivery.

Goal 4: Prevent HIV transmission to an uninfected partner when trying to conceive

HIV-discordant couples who desire pregnancy should receive appropriate counseling about methods to minimize risk of transmission to the uninfected partner while trying to conceive. There are a number of effective methods and techniques, which are beyond the scope of this review. Key components of all methods are to screen for and treat sexually transmitted infections in both partners and to use effective antiretroviral therapy and attain maximal viral suppression in the HIV-positive partner.

Antiretroviral therapy for the HIV-infected partner significantly reduced the risk of HIV transmission by 96% in the HIV Prevention Trials Network 052 trial.³⁰ Of note: this reduction was the result of both risk-reduction counseling and antiretroviral therapy. This was the first randomized clinical trial to demonstrate that antiretroviral therapy in those with some preserved immune function (CD4 counts 350–500 cells/mm³) in conjunction with risk-reduction counseling can reduce HIV transmission to an uninfected partner.

Vaginal insemination without intercourse is another option for female-positive couples. The man ejaculates into a condom without spermicide, and the contents are introduced with a non-needle syringe or turkey baster. This can be done at home and confers no risk to the uninfected male partner.³¹ Chances of pregnancy can be maximized by insemination during the most fertile days of the menstrual cycle.

Preexposure prophylaxis combined with timed intercourse. In a study in Switzerland, the infected male partner was given antiretroviral therapy to suppress his viral load to less than 50 copies/mL for at least 6 months, and luteinizing hormone was measured every day in the urine of the noninfected female partner. When the urinary luteinizing hormone level reached a peak, the woman received a dose of tenofovir in the morning, the couple had unprotected intercourse, and the woman took a second dose the next morning. In 53 cases, none of the female partners seroconverted for HIV.³²

Health care providers need to document and update the relationship status, partner HIV status, and fertility desires of their HIV patients, both men and women, on a regular basis. Patient education should include awareness of referrals and options to help safely conceive when desired and achieve effective contraception when not.³³

WHEN HIV-POSITIVE WOMEN BECOME PREGNANT

Screening for HIV during pregnancy

The CDC recommends prenatal screening for HIV in the first trimester or at entry into prenatal care. A repeat HIV test should be offered in the third trimester for women at risk of acquiring HIV, for women who have signs or symptoms of early HIV infection, in health care settings where prenatal testing yields at least 1 case of HIV infection per 1,000 women screened, and in areas of high HIV incidence. If women present to labor and delivery with unknown HIV status, rapid HIV testing should be done.⁹

If a woman acquires HIV during pregnancy, the infection may not be detected and may be transmitted to the infant at birth. From 2002 to 2006 in New York State, 3,396 HIV-exposed babies were born. Of these, 9 (22%) of 41 infants born to mothers who acquired HIV during pregnancy became infected, compared with 1.8% of those born to mothers who acquired HIV before pregnancy. Maternal acquisition of HIV during pregnancy was documented in only 1.3% of perinatal HIV exposures, but it was associated with 9 (13.8%) of the 65 perinatal transmission cases.³⁴

Providers should be aware of the signs and symptoms of acute HIV infection and should have a low threshold for repeating HIV testing at any time during pregnancy. It has been estimated that 40% to 90% of patients with acute HIV infection experience fever, lymphadenopathy, pharyngitis, skin rash, myalgia, arthralgia, or other symptoms.³⁵ Providers often do not recognize acute HIV infection, however, because the symptoms are similar to those of other common illnesses. Also, some individuals with the condition have no symptoms.

Antiretroviral therapy during pregnancy

In a landmark study, AIDS Clinical Trial Group 076 demonstrated that zidovudine monotherapy given during pregnancy, labor, and delivery and to the newborn reduced the risk of HIV transmission to the infant by 67%, from 25% to 8%.³⁶ Other studies demonstrated that combination therapy further decreased the risk of HIV transmission to 1% to 2%.³⁷

The US Department of Health and Human Services recommends that all HIV-positive women who are pregnant receive effective combination antiretroviral therapy regardless of CD4 count to minimize the risk of mother-to-child transmission.³⁷

The goals of HIV treatment during pregnancy are to maintain the woman’s health, restore her immune system, suppress viral replication, and decrease the risk of perinatal transmission. The preferred antiretroviral therapy for pregnant women differs from that for nonpregnant women and is based on evolving experience and information about safety, efficacy, and tolerability in pregnancy (Table 8). A woman who presents for prenatal care on a suppressive regimen should continue that regimen as long as she can tolerate it because there is a risk of losing virologic control when switching regimens, and this may increase the risk of perinatal transmission.³⁷

Physiologic changes that occur during pregnancy may alter drug disposition, which could potentially lead to decreased drug exposure. Some of the changes include an increase in total body water, decreased protein binding, induction of hepatic metabolic pathways, and increased clearance of drugs eliminated by the kidneys.³⁸ These changes may be associated with incomplete virologic suppression, virologic failure, or development of drug resistance, so altered doses of some antiretroviral drugs or careful monitoring of viral load should be considered, particularly in the second and third trimester.

Delivery

Women who have a viral load greater than 1,000 copies/mL near the end of pregnancy should undergo a cesarean delivery at 38 weeks and, before surgery, should receive intravenous zidovudine to reduce the risk of perinatal transmission. For women with viral loads below the threshold of 1,000 copies/mL, there is no proven added benefit to cesarean delivery, and in this situation it should be performed only for standard obstetric indications. Antiretroviral regimens should be continued during labor.³⁷

HIV IN OLDER ADULTS

By 2015, approximately 50% of people with HIV will be over age 50.³⁹ Unfortunately, older people and their providers often underestimate their risk of acquiring HIV. Many older people are newly single and may engage in sexual activity with new partners. Also, older people may be reluctant to use condoms as the need for contraception is past.^40,41

Baseline HIV RNA levels tend to be higher and CD4 cell counts lower in patients diagnosed with HIV at older ages. These observations support previous ones that older HIV-infected patients may have advanced HIV disease at the time of diagnosis, perhaps in part due to delayed testing.⁴² Other possible factors are limited income, comorbid illness, polypharmacy, and insufficient data on drug interactions in the elderly.^41,42

A prompt diagnosis is important for older patients because HIV may accelerate aging, and aging may speed up HIV progression. Studies have shown that aging is associated with more rapid progression to AIDS, particularly among people who are older than 40 at seroconversion.⁴³ Other studies have reported that older patients have better virologic responses to antiretroviral therapy but have a blunted immune response, more AIDS-defining events, and a higher mortality rate than younger patients.⁴²

More than 30 years into the human immunodeficiency virus (HIV) epidemic, our understanding of the needs of women living with this virus continues to evolve. In the early years of the epidemic, managing HIV was all about preventing death and treating opportunistic infections. But now it is also about enabling patients to live long, healthy, and productive lives and preventing new HIV infections. In women, these goals can only be achieved by paying careful attention to sex-specific issues.

See related editorial

As a result of longer survival, HIV-infected persons are increasingly developing common health problems that also affect the general population and that require screening, management, and monitoring by primary care providers. Because people infected with HIV are typically seen by both an HIV specialist and a primary care provider, HIV specialists need to be familiar with primary care issues and primary care providers need to be familiar with HIV care recommendations in order to provide optimal care.

AFRICAN AMERICAN WOMEN BEAR A DISPROPORTIONATE BURDEN

In the United States, HIV was first reported in women in 1983 among those who had been steady sexual partners of males with acquired immune deficiency syndrome.¹ Although men with HIV still outnumber women, the number of women with HIV has increased rapidly. At the end of 2010 an estimated one in four people with HIV in the United States was female.²

African American women bear a disproportionate burden of the disease (Table 1).³ In 2010, women accounted for an estimated 9,500 (20%) of the approximately 45,000 new infections occurring in the United States. Of these newly infected women, 64% were black, 18% were white, and 15% were Hispanic. Yet blacks make up only about 12% of the US population, whites make up 68%, and Hispanics 14%.

Regardless of race or ethnicity, unprotected heterosexual contact is the most common mode of transmission of HIV in women.²

Although the overall rates of HIV infection in the United States are relatively low, certain areas of the country have rates similar to those in sub-Saharan Africa, where most HIV-infected people reside.⁴ The HIV Prevention Trials Network found that the incidence of HIV infection in US women living in these “hot spots,” with high rates of poverty and HIV, was 0.32% per year. Compare this with the 2009 estimate of HIV incidence in the general population of US black women of similar age (0.05% per year) and the adult incidence rates in Congo (0.28% per year) and Kenya (0.53% per year).⁵ To better understand the epidemiology of HIV infection in women and concentrate our prevention efforts, we need to focus on these hot spots.

Misinformation abounds in these hot spots, as does disease. In a survey of residents of the South Side Chicago Housing Authority facilities,⁶ many were aware that effective antiretroviral therapy existed, but one-fourth thought that there was an effective HIV vaccine, and 13% thought there was a cure.

In the early years, an HIV diagnosis was essentially a death sentence. Samji et al⁷ estimated that life expectancy of patients who were prescribed antiretroviral therapy in the United States and Canada increased from 36.1 years in 2000–2002 to 51.4 years in 2006–2007, with the greatest increases in those who started with a baseline CD4 count above 350 cells/mm³. Now, a 20-year-old HIV-positive person with a CD4 count greater than 350 cells/mm³ can expect to live into his or her early 70s.

But not all patients achieve these benefits. In 2009, despite major advances in diagnosis and treatment, HIV was the fourth leading cause of death among African American women ages 25 to 44, causing about 800 deaths, or 9% of all deaths in this group.⁸

TEST ALL, UNLESS THEY OPT OUT

Testing is vital in efforts to prevent and treat HIV infection. In 2006, the US Centers for Disease Control and Prevention (CDC) recommended that everyone between the ages of 13 and 64 be screened for HIV regardless of risk.⁹

The CDC recommends an opt-out strategy.⁹ Rather than ask a patient whether he or she wants to be tested for HIV, the provider says something like, “I advise all of my patients to have an HIV test; as long as you have no objection, we will send you to the lab to have it done.” This approach reduces barriers to HIV testing by eliminating pretest counseling and by making HIV testing routine and the standard of care. Separate consent is not required—clinicians just need to document whether the patient has accepted or declined the test.

Testing should be offered at least once and can be done in any health care setting, including primary care offices and clinics, emergency rooms, health departments, and urgent care centers.⁹ Patients at higher risk (injection drug users and their sex partners; people who exchange sex for money or drugs; sex partners of HIV-infected people; men who have sex with men; and heterosexuals who themselves or whose sex partners have had more than one sex partner since their most recent HIV test) should receive repeat screening annually.

HIV testing should also be offered to all pregnant women at entry into care and again in the third trimester. This strategy is cost-effective even in areas of low prevalence.⁹ Since 2006, other professional organizations have made HIV testing recommendations as well (Table 2).^9–12

A cost-effectiveness analysis suggested that routine opt-out testing is economically justified if the prevalence of HIV is greater than 0.2%.¹³

HIV-POSITIVE WOMEN NEED ROUTINE GYNECOLOGIC CARE

It is important for women with HIV to receive routine gynecologic care. Women with HIV have gynecologic problems similar to those of all women; however, they may be more vulnerable to certain conditions such as human papillomavirus (HPV) infection, which may be related to HIV disease or associated immunosuppression. In addition, pregnancy and family planning pose special challenges in this group.¹⁴

Cervical cancer screening

Effective screening and timely treatment of precancerous cervical lesions are key in preventing cervical cancer in women with or without HIV.

Persistent infection with HPV is necessary for the development of precancerous lesions as well as invasive cervical cancer. Most new cases of HPV infection in the general population resolve spontaneously within 2 years. However, in HIV-infected women, HPV infection is more likely to persist and progress to precancerous lesions of the cervix. This association is strongest in women with more compromised immune function as reflected by low CD4 cell counts and high viral loads.¹⁴ Women with HIV have higher rates of infection with high-risk HPV strains and of cervical intraepithelial neoplasia compared with their HIV-negative counterparts.¹⁴ The incidence of cervical cancer is five to six times higher in HIV-infected women in the United States than in the general population.¹⁵

According to guidelines from the Infectious Diseases Society of America,¹⁶ the American College of Obstetricians and Gynecologists,¹⁰ the CDC,¹⁷ and the American Cancer Society,¹⁸ all HIV-infected women should undergo cervical Papanicolaou (Pap) screening upon initiation into care, and this test should be repeated at 6 months and then annually if the results are normal. Patients with abnormalities on the Pap test should undergo colposcopy and, possibly, also biopsy. These abnormalities include atypical squamous cells of unknown significance and higher-grade lesions.¹⁶

Nearly one-fourth of HIV-positive women do not receive annual Pap smears despite engagement in care.¹⁹ This is unacceptable, because half of the cases of cervical cancer diagnosed in the United States are in women who never received appropriate screening, and an additional 10% are in women who have not been screened in the previous 5 years.¹⁹

In HIV-infected women who have had a total hysterectomy, whether to continue Pap testing depends on their history before the surgery. Continued vaginal Pap smear screening is recommended after hysterectomy (including removal of the cervix) in HIV-infected women who have a history of cervical intraepithelial neoplasia grades 2 or 3 or invasive cancer.^10,17,20

TREATING HIV IN WOMEN: SPECIAL CONSIDERATIONS

Because it is not yet possible to eradicate the HIV virus, the goals of antiretroviral therapy are to reduce HIV-associated morbidity and mortality, to restore and preserve immune function, to suppress viral load, and to prevent sexual and, in women, perinatal transmission of the virus.²¹

Antiretroviral therapy is recommended for all HIV-infected patients regardless of the CD4 count, although the strength of recommendation is weaker with higher CD4 counts (Table  3).²¹ The recommendations for starting antiretroviral therapy and the goals of treatment are the same for men and women. Table 4 summarizes the recommendations for adolescents and adults who are new to treatment.²¹ For women, additional factors that should be taken into account when considering a regimen include pregnancy potential and whether the drugs chosen for the regimen are considered safe in pregnancy.

Since the early years of the HIV epidemic, researchers have debated whether women attain the same benefits from antiretroviral therapy as men. US Food and Drug Administration investigators performed a meta-analysis of the efficacy outcomes in women in studies of antiretroviral drugs published between 2000 and 2008. They included randomized clinical trials reporting at least 48-week efficacy outcomes, with viral suppression defined as HIV RNA less than 50 copies/mL. The combined database included 40 trials of 16 drugs from 7 drug classes with a total of 20,328 HIV-positive participants. Overall, there were no clinically or statistically significant differences between the sexes in 48-week efficacy outcomes or in rates of trial discontinuation due to adverse events, loss to follow-up, or death.²²

Antiretroviral therapy may, however, cause different adverse effects in women than in men. For example:

Nevirapine, a nonnucleoside reverse transcriptase inhibitor, has been associated with the development of a rash and potentially life-threatening hepatotoxicity, more commonly in women than in men and at lower CD4 counts in women. This resulted in recommendations²¹ to avoid starting a nevirapine-containing regimen in women with CD4 counts greater than 250 cells/mm³ and in men with CD4 counts greater than 400 cells/mm³.

Ritonavir has been observed to cause a higher incidence of nausea and vomiting in women and a higher incidence of diarrhea in men. These are thought to be due to differences between men and women in weight and pharmacokinetics.²³

PRECONCEPTION COUNSELING FOR HIV-POSITIVE WOMEN

Preconception counseling is an essential component of both primary and preventive care and should be considered the standard of care for all women of reproductive age who have HIV.²⁴ Health care providers who fully understand the impact of HIV infection and associated comorbidities upon a woman’s reproductive health, fertility desires, and family planning needs are better prepared to assist in their patients’ reproductive health decisions.

The first few weeks of pregnancy are the most critical period in fetal development. During this time, a woman should be healthy and avoid any activities or substances that could cause adverse maternal or fetal outcomes. However, most patients present for prenatal care after this critical time period—thus the need for preconception counseling. Both the Infectious Diseases Society of America and the HIV Medicine Association recommend that all HIV-infected women of childbearing age be asked about their pregnancy plans and desires at the start of care and routinely thereafter.¹⁶

The goals of preconception care in women with HIV are to prevent unintended pregnancy, optimize maternal health before pregnancy, optimize pregnancy outcomes for mother and fetus, prevent perinatal HIV transmission, and prevent HIV transmission to an HIV-negative partner when trying to conceive.²⁴

Goal 1: Prevent unintended pregnancy

Nearly half of all pregnancies in the United States are unintended.²⁵ Moreover, the Women’s Interagency HIV Study²⁶ showed that women with HIV are underusing effective contraception. In the Medical Monitoring Project, 85% of the women who had been pregnant since being diagnosed with HIV said that at least one pregnancy was unplanned.²⁷

The consequences of unintended and unplanned pregnancies are serious and add significant burden to women, men, and families. Women who do not wish to become pregnant should be advised to use an effective method of contraception.

Contraception

Contraception use varies worldwide. Factors affecting its use include the methods available, patient choice, current health conditions, religious beliefs, perception of method effectiveness, and side effects.²⁴

The Women’s Interagency HIV Study evaluated trends in contraception use from 1998 to 2010. Condoms were the most common form of contraception, and their use changed little over time. Fewer than 15% of women with HIV used no contraception. The use of long-acting reversible contraception, including injectable progestins, implants, and intrauterine devices, which minimize the need for user adherence, increased among HIV-negative women but not among HIV-positive women.²⁸

The World Health Organization states that all available methods are safe for women with HIV except for spermicides with or without a diaphragm, as there is evidence linking the use of spermicides to an increased risk of HIV transmission (Table 5).²⁹

Some antiretroviral drugs may reduce the effectiveness of some contraceptives (Table 6); however, recommendations are based on pharmacokinetic studies, not on outcome studies. Condoms should be recommended not only to protect against pregnancy, but also to protect against sexually transmitted infections.

Goal 2: Optimize maternal health before pregnancy

Maternal health should be optimized before conceiving to reduce the risk of pregnancy-related morbidities and poor birth outcomes. This includes screening for other infections and ensuring that other comorbidities, such as hypertension, diabetes, substance abuse, and mental illness, are well managed with medications that are safe to use in pregnancy (Table 7).

Goal 3: Prevent perinatal HIV transmission

Educating the patient about perinatal transmission is a fundamental component of preconception counseling. Topics that need to be addressed are transmission risk and methods to reduce the risk, including not breastfeeding after delivery.

Goal 4: Prevent HIV transmission to an uninfected partner when trying to conceive

HIV-discordant couples who desire pregnancy should receive appropriate counseling about methods to minimize risk of transmission to the uninfected partner while trying to conceive. There are a number of effective methods and techniques, which are beyond the scope of this review. Key components of all methods are to screen for and treat sexually transmitted infections in both partners and to use effective antiretroviral therapy and attain maximal viral suppression in the HIV-positive partner.

Antiretroviral therapy for the HIV-infected partner significantly reduced the risk of HIV transmission by 96% in the HIV Prevention Trials Network 052 trial.³⁰ Of note: this reduction was the result of both risk-reduction counseling and antiretroviral therapy. This was the first randomized clinical trial to demonstrate that antiretroviral therapy in those with some preserved immune function (CD4 counts 350–500 cells/mm³) in conjunction with risk-reduction counseling can reduce HIV transmission to an uninfected partner.

Vaginal insemination without intercourse is another option for female-positive couples. The man ejaculates into a condom without spermicide, and the contents are introduced with a non-needle syringe or turkey baster. This can be done at home and confers no risk to the uninfected male partner.³¹ Chances of pregnancy can be maximized by insemination during the most fertile days of the menstrual cycle.

Preexposure prophylaxis combined with timed intercourse. In a study in Switzerland, the infected male partner was given antiretroviral therapy to suppress his viral load to less than 50 copies/mL for at least 6 months, and luteinizing hormone was measured every day in the urine of the noninfected female partner. When the urinary luteinizing hormone level reached a peak, the woman received a dose of tenofovir in the morning, the couple had unprotected intercourse, and the woman took a second dose the next morning. In 53 cases, none of the female partners seroconverted for HIV.³²

Health care providers need to document and update the relationship status, partner HIV status, and fertility desires of their HIV patients, both men and women, on a regular basis. Patient education should include awareness of referrals and options to help safely conceive when desired and achieve effective contraception when not.³³

WHEN HIV-POSITIVE WOMEN BECOME PREGNANT

Screening for HIV during pregnancy

The CDC recommends prenatal screening for HIV in the first trimester or at entry into prenatal care. A repeat HIV test should be offered in the third trimester for women at risk of acquiring HIV, for women who have signs or symptoms of early HIV infection, in health care settings where prenatal testing yields at least 1 case of HIV infection per 1,000 women screened, and in areas of high HIV incidence. If women present to labor and delivery with unknown HIV status, rapid HIV testing should be done.⁹

If a woman acquires HIV during pregnancy, the infection may not be detected and may be transmitted to the infant at birth. From 2002 to 2006 in New York State, 3,396 HIV-exposed babies were born. Of these, 9 (22%) of 41 infants born to mothers who acquired HIV during pregnancy became infected, compared with 1.8% of those born to mothers who acquired HIV before pregnancy. Maternal acquisition of HIV during pregnancy was documented in only 1.3% of perinatal HIV exposures, but it was associated with 9 (13.8%) of the 65 perinatal transmission cases.³⁴

Providers should be aware of the signs and symptoms of acute HIV infection and should have a low threshold for repeating HIV testing at any time during pregnancy. It has been estimated that 40% to 90% of patients with acute HIV infection experience fever, lymphadenopathy, pharyngitis, skin rash, myalgia, arthralgia, or other symptoms.³⁵ Providers often do not recognize acute HIV infection, however, because the symptoms are similar to those of other common illnesses. Also, some individuals with the condition have no symptoms.

Antiretroviral therapy during pregnancy

In a landmark study, AIDS Clinical Trial Group 076 demonstrated that zidovudine monotherapy given during pregnancy, labor, and delivery and to the newborn reduced the risk of HIV transmission to the infant by 67%, from 25% to 8%.³⁶ Other studies demonstrated that combination therapy further decreased the risk of HIV transmission to 1% to 2%.³⁷

The US Department of Health and Human Services recommends that all HIV-positive women who are pregnant receive effective combination antiretroviral therapy regardless of CD4 count to minimize the risk of mother-to-child transmission.³⁷

The goals of HIV treatment during pregnancy are to maintain the woman’s health, restore her immune system, suppress viral replication, and decrease the risk of perinatal transmission. The preferred antiretroviral therapy for pregnant women differs from that for nonpregnant women and is based on evolving experience and information about safety, efficacy, and tolerability in pregnancy (Table 8). A woman who presents for prenatal care on a suppressive regimen should continue that regimen as long as she can tolerate it because there is a risk of losing virologic control when switching regimens, and this may increase the risk of perinatal transmission.³⁷

Physiologic changes that occur during pregnancy may alter drug disposition, which could potentially lead to decreased drug exposure. Some of the changes include an increase in total body water, decreased protein binding, induction of hepatic metabolic pathways, and increased clearance of drugs eliminated by the kidneys.³⁸ These changes may be associated with incomplete virologic suppression, virologic failure, or development of drug resistance, so altered doses of some antiretroviral drugs or careful monitoring of viral load should be considered, particularly in the second and third trimester.

Delivery

Women who have a viral load greater than 1,000 copies/mL near the end of pregnancy should undergo a cesarean delivery at 38 weeks and, before surgery, should receive intravenous zidovudine to reduce the risk of perinatal transmission. For women with viral loads below the threshold of 1,000 copies/mL, there is no proven added benefit to cesarean delivery, and in this situation it should be performed only for standard obstetric indications. Antiretroviral regimens should be continued during labor.³⁷

HIV IN OLDER ADULTS

By 2015, approximately 50% of people with HIV will be over age 50.³⁹ Unfortunately, older people and their providers often underestimate their risk of acquiring HIV. Many older people are newly single and may engage in sexual activity with new partners. Also, older people may be reluctant to use condoms as the need for contraception is past.^40,41

Baseline HIV RNA levels tend to be higher and CD4 cell counts lower in patients diagnosed with HIV at older ages. These observations support previous ones that older HIV-infected patients may have advanced HIV disease at the time of diagnosis, perhaps in part due to delayed testing.⁴² Other possible factors are limited income, comorbid illness, polypharmacy, and insufficient data on drug interactions in the elderly.^41,42

A prompt diagnosis is important for older patients because HIV may accelerate aging, and aging may speed up HIV progression. Studies have shown that aging is associated with more rapid progression to AIDS, particularly among people who are older than 40 at seroconversion.⁴³ Other studies have reported that older patients have better virologic responses to antiretroviral therapy but have a blunted immune response, more AIDS-defining events, and a higher mortality rate than younger patients.⁴²

Continued progress in understanding the pathophysiology of acute respiratory distress syndrome (ARDS) is translating into changes in the way we diagnose and manage it. Over the past 20 years, low tidal volume,¹ positive end-expiratory pressure (PEEP),² and fluid restriction³ have become the standard of care. A multidisciplinary approach, including targeted use of sedatives, early mobilization, and protocols for weaning from the ventilator, has also brought about substantial changes in ARDS management and its outcomes.^4–6

In this article, we review the most relevant articles about ARDS in the last 5 years. We include the new definition of ARDS and studies of ventilatory and nonventilatory therapies that have implications in managing patients with ARDS.

A STANDARDIZED APPROACH

ARDS is characterized by damage to the alveolar architecture, severe hypoxemia, and bilateral parenchymal opacities.

The working definition of ARDS developed in 1994 by the American-European Consensus Conference (AECC) was the basis for enrollment in most of the landmark trials and observational studies over the past 20 years.^7,8 However, it was limited in its reliability and validity.

An updated definition

In 2011, the ARDS Definition Task Force, using a novel consensus process, updated the ARDS definition,⁹ focusing on its feasibility, reliability, and validity in predicting response to therapies and outcomes in ARDS. This new “Berlin” definition is not substantially different from the old, but defines the criteria more specifically:

• Bilateral opacities, unexplained by nodules, atelectasis, or effusion, on chest radiography or computed tomography
• New or worsening respiratory symptoms, or a clinical insult associated with ARDS within 7 days of diagnosis
• Objective assessment of cardiac function (eg, with echocardiography) to exclude cardiogenic pulmonary edema
• Hypoxemia, with a partial pressure of arterial oxygen divided by the percentage of inspired oxygen (PaO₂/FiO₂ ratio) of 300 mm Hg or less despite noninvasive or invasive mechanical ventilation with PEEP or continuous positive airway pressure (CPAP) of at least 5 cm H₂O.

In addition, the new definition classifies the severity of disease on the basis of the degree of hypoxemia, ie, the PaO₂/FiO₂ ratio:

• Mild: PaO₂/FiO₂ ratio > 200 and ≤ 300 mm Hg
• Moderate: PaO₂/FiO₂ ratio > 100 and ≤ 200 mm Hg
• Severe: PaO₂/FiO₂ ratio ≤ 100 mm Hg.

The term “acute lung injury” has been eliminated, as has the previous criterion of a pulmonary artery wedge pressure of 18 mm Hg or less.

The panel also evaluated four ancillary variables for predicting outcomes in severe ARDS:

• Compliance of the respiratory system less than or equal to 40 mL/cm H₂O
• Radiographic severity (involvement of three or four quadrants on chest radiography)
• PEEP of 10 cm H₂O or greater
• Corrected expired volume 10 L/min or greater.

The task force evaluated the reliability and validity of this definition in a meta-analysis of 4,400 patients previously enrolled in randomized controlled trials or observational studies.

Findings. The Berlin definition predicted the risk of death better than the AECC definition. The mortality rate increased with the severity of ARDS, from 27% with mild disease to 32% with moderate disease to 45% with severe disease. The four ancillary variables did not contribute to the predictive validity of severe ARDS for mortality and were removed from the definition.

Thille et al¹⁰ retrospectively reviewed autopsy findings from 712 patients and found that the new definition identified a homogeneous group who had severe ARDS.¹⁰

Conclusions. The new definition may overcome some of the limitations of the old one, but it needs to be validated in clinical practice, especially its ability to predict death.

VENTILATORY SUPPORT

Prompt recognition, lung-protective ventilation, and a conservative fluid strategy remain the cornerstones of ARDS management. However, other strategies are being tested.

Prone-position ventilation in severe ARDS: The right therapy in a specific population

Prone-position ventilation was first described almost 30 years ago, but it has been used inconsistently in clinical practice.

Physiologic and observational studies indicated that prone positioning might improve survival in patients with ARDS, but several randomized trials failed to demonstrate any positive effect on outcomes.^11,12 Some trials also reported a higher rate of complications with this intervention.¹³ However, meta-analyses suggested that prone-position ventilation might have a beneficial effect in patients with severe ARDS (defined as a PaO₂/FiO₂ ratio ≤ 100 mm Hg).¹⁴

In view of these findings, investigators conducted a trial of prone-position ventilation exclusively in patients with severe ARDS.

The PROSEVA study

The Proning Severe ARDS Patients (PROSEVA) study was a randomized controlled trial designed to determine whether prone-position ventilation, applied early, would improve outcomes in patients with severe ARDS.¹⁵

In PROSEVA, 466 patients with severe ARDS (defined as a PaO₂/FiO₂ ratio < 150 mm Hg, FiO₂ ≥ 60%, and PEEP ≥ 5 cm H₂O) underwent either at least 16 hours of prone positioning or were left in the supine position after 12 to 24 hours of initial conventional mechanical ventilation. The patients were recruited from centers in France and Spain where prone-position ventilation had been used in daily practice for more than 5 years.

The primary outcome studied was the rate of death at 28 days. The secondary end points were the death rate at day 90, rates of successful extubation, the length of stay in the intensive care unit, and complications.

Findings. At study entry, the patients in the supine group were sicker, more of them required a vasopressor, and fewer of them were receiving neuromuscular blocking agents than those in the prone group. These baseline differences may have influenced the outcomes; the unadjusted 28-day mortality rate was 16.0% in the prone group compared with 32.8% in the supine group (P < .001). However, the hazard ratio for death with prone positioning was 0.39 (95% confidence interval [CI] 0.25–0.63) even after adjusting for severity and the use of vasopressors and neuromuscular blocking agents. Prone-position ventilation was not associated with a higher incidence of complications, and the rate of successful extubation was higher.

Conclusions. In patients with severe ARDS, early use of prolonged prone positioning significantly decreased the 28-day and 90-day mortality rates. This trial has made prone positioning one of the strategies in managing patients with early severe ARDS. To minimize complications such as pressure ulcers and line or tube dislodgement, personnel caring for these patients must follow a protocol and undergo specific training.

These results were corroborated by a meta-analysis by Beitler et al¹⁶ that found a significant decrease in mortality rate with prone-position ventilation even in older studies when lung-protective ventilation strategies were separated from high-tidal-volume ventilation.

High-frequency oscillatory ventilation: No benefit in two trials

Observational data and experimental studies suggested that high-frequency oscillatory ventilation (HFOV) is superior to conventional mechanical ventilation in ARDS patients.^17,18 However, outdated and cumbersome equipment, lack of protocols, and a lack of high-quality evidence led to limited and inconsistent use of HFOV, mainly as a rescue therapy in ARDS.¹⁹

Over the last few years, HFOV has been gaining acceptance, especially earlier in the course of ARDS.²⁰ After preliminary clinical trials reported promising results, two trials conducted in Canada and the United Kingdom compared HFOV vs conventional mechanical ventilation in patients with ARDS.

The OSCAR study

The Oscillation in ARDS (OSCAR) study²¹ was a “pragmatic” trial²² (ie, it had minimal exclusion criteria) of the safety and effectiveness of HFOV as a primary ventilatory strategy for ARDS. It included 795 patients randomized to receive conventional ventilation (n = 397) or HFOV (n = 398). Research centers followed detailed algorithms for HFOV management and adopted their usual practice for conventional ventilation. Medical care was given according to the clinician’s judgment.

The primary outcome studied was survival at 30 days. The secondary outcomes were all-cause mortality in the intensive care unit and the hospital, duration of mechanical ventilation, and use of antimicrobial, sedative, vasoactive, and neuromuscular-blocking drugs.

Findings. The patient baseline characteristics were similar in both groups.

There was no significant difference in intensive care unit mortality rates, hospital mortality rates, or mortality rates at 30 days (41.7% in the HFOV group vs 41.1% in the conventional ventilation group; P = .85, 95% CI 6.1–7.5) even after adjustments for center or severity of illness.

The duration of mechanical ventilation was similar in both groups (14.9 ± 13.3 days in the HFOV group vs 14.1 ± 13.4 days in the conventional ventilation group, P = .41). However, sedatives and neuromuscular-blocking drugs were used more often and longer in the HFOV group than in the conventional ventilation group. There was no difference in the use of vasoactive or antimicrobial medications.

Conclusions. This multicenter randomized control trial did not demonstrate any benefit from using HFOV for routine management of ARDS. Its pragmatic design made it less likely to reach a firm conclusion,²² but it at least made a case against routinely using HFOV in patients with ARDS.

The OSCILLATE study

The Oscillation for Acute Respiratory Distress Syndrome Treated Early (OSCILLATE) study²³ assessed the safety and efficacy of HFOV as a treatment for early-onset moderate-to-severe ARDS.

The inclusion criteria were similar to those in the OSCAR trial except that pulmonary symptoms had to be present less than 2 weeks and ARDS assessment was done under standard ventilator settings. As this was an efficacy trial, it had more exclusion criteria than the OSCAR trial. A total of 548 patients were randomized to receive conventional ventilation (n = 273) or HFOV (n = 275). The baseline characteristics were similar between groups.

Conventional ventilation was given according to a protocol used in an earlier trial² and included recruitment maneuvers. HFOV was given in centers that had experience in this treatment, and there were protocols for ventilation management, hemodynamic optimization, and weaning. All other care was left to the clinician’s choice.

The primary outcome studied was in-hospital mortality. The investigators also evaluated whether there were interactions between the treatment and baseline severity of lung injury and center experience with HFOV.

Findings. The trial was stopped after an interim analysis found that HFOV might be harmful, although the statistical threshold for stopping was not reached. The in-hospital mortality rate was 47% in the HFOV group and 35% in the control group (relative risk of death with HFOV 1.33, 95% CI 1.09–1.64, P = .005). HFOV was worse than conventional ventilation regardless of the severity of disease or center experience. The HFOV group had higher mean airway pressures but similar FiO₂ compared with the conventional ventilation group.

The HFOV group received significantly more vasopressors, sedatives, and neuromuscular blockers. This group’s fluid balance was higher as well, but not significantly so. Refractory hypoxemia (defined as PaO₂ < 60 mm Hg for 1 hour with an FiO₂ of 1.0 and neuromuscular blockade) was more frequent in the conventional ventilation group, but the number of deaths in the subgroup with refractory hypoxemia was similar with either treatment.

Conclusions. This multicenter randomized controlled trial demonstrated that HFOV was harmful when used routinely to manage ARDS. The trial’s protocol was based on the results of a pilot study carried out by the same investigators, which provided the best evidence available regarding the safety of HFOV at that time.

The results of the OSCAR and OSCILLATE trials have quelled enthusiasm for early, routine use of HFOV in ARDS. Although there are concerns that the protocol (ie, the way HFOV was implemented) rather than HFOV itself may have led to worse outcomes, there is no signal to support its routine use. We need further studies to define if it remains a viable rescue therapy.

Extracorporeal membrane oxygenation: Is it a viable option in severe ARDS?

Extracorporeal membrane oxygenation (ECMO) uses cardiopulmonary bypass technology to provide gas exchange. In patients with severe hypoxemia, ECMO can ensure adequate oxygenation and ventilation while ensuring the optimization of lung-protective ventilation. But ECMO was never as successful in adults with ARDS as it was in children and neonates.²⁴

The first two trials of ECMO in ARDS^24,25 reported equal or worse survival rates compared with conventional ventilation, and the overall mortality rate in these studies was staggeringly high. However, these studies were carried out before the era of lung-protective ventilation and at a time when ECMO technology was relatively primitive.

With new technology such as venovenous circuits and smaller cannulas, ECMO has gained more acceptance. It was used in patients with severe or refractory hypoxemia associated with ARDS during the H1N1 pandemic.^26,27

The CESAR trial

The Conventional Ventilatory Support Versus Extracorporeal Membrane Oxygenation for Severe Adult Respiratory Failure (CESAR) trial²⁸ assessed the safety, clinical efficacy, and cost-effectiveness of ECMO in managing severe ARDS. It compared best standard practice vs a protocol that included ECMO. The trial was conducted from 2001 to 2006.

Patients with severe ARDS, as defined by a Murray score²⁹ greater than 3 or uncompensated hypercapnea, were prospectively randomized and recruited from an ECMO center and 148 tertiary intensive care units and referral hospitals in England. This was a pragmatic trial, with minimal exclusion criteria (essentially, mechanical ventilation with high pressures and high FiO₂ for more than 7 days, intracranial bleeding, or contraindication to heparinization).

A total of 180 patients were randomized in a one-to-one ratio to receive ECMO or conventional management. The ventilator management in the conventional treatment group was not done according to a protocol but in general was low-volume and low-pressure. All patients randomized to ECMO were transferred to the ECMO center and treated according to a standardized ventilation protocol. After 12 hours, if predefined goals were not reached, venovenous ECMO was started. Patients assigned to conventional management could not cross over to ECMO.

The primary outcomes were death or severe disability at 6 months after randomization, and cost-effectiveness. The secondary outcomes were hospital resource use (eg, rescue techniques, length of stay, duration of ECMO) and health status after 6 months.

Findings. The groups were similar at baseline. Sixty-eight (75%) of the 90 patients randomized to receive ECMO actually received it. Of the 22 patients who did not receive ECMO, 16 (18% of the 90) improved on conventional therapy, 5 (6%) died during or before transfer, and 1 could not receive heparin.

Two patients had severe complications in the ECMO group: one had an arterial puncture, and one had an oxygen delivery failure during transport. In each case, these events contributed to the death of the patient.

More patients in the ECMO group received lung-protective ventilation, 84 (93%) vs 63 (70%).

The primary outcome, ie, death or severe disability at 6 months, occurred in 33 (37%) of the 90 patients in the ECMO group and in 46 (53%) of the patients in the conventional management group (relative risk 0.69, 95% CI 0.05–0.97, P = .03). More patients in the ECMO group survived, but the difference was not statistically significant (relative risk of death 0.73, 95% CI 0.52–1.03, P = .07). The most common cause of death in the ECMO group was multiorgan failure (42%), whereas in the conventional management group, the most common cause of death was respiratory failure (60%).

Length of stay in the hospital and in the critical care unit and health care costs were double for patients in the ECMO group. There was no difference in quality-of-life markers at 6 months in the survivors.

Conclusions. This pragmatic trial demonstrated that a protocol that includes ECMO could improve survival rates in ARDS.

Of note, the ECMO group got care in regional centers that used protocols. Therefore, in interpreting the results of this trial, we have to consider that being in a center with protocol-specified care for ARDS could drive some of the difference in mortality rates.

Regardless, this trial demonstrated that ECMO is feasible and led to better outcomes than expected. The findings were encouraging, and spurred the use of ECMO in severe ARDS during the 2009 H1N1 pandemic. Two propensity-matched studies and a number of case series reported a survival benefit associated with the use of ECMO in patients with severe ARDS.^27,30

A recent meta-analysis also reported that ECMO might lower the mortality rate in ARDS; however, the patients in the H1N1 pandemic were younger and usually had isolated respiratory failure.³¹

The success of ECMO has opened new possibilities in the management of ARDS. As the technology improves and our experience increases, ECMO will likely gain more acceptance as a treatment for severe ARDS.

Airway pressure release ventilation

The use of airway pressure release ventilation and other ventilator modalities in ARDS is not supported by current evidence, though results of clinical trials may influence our practice in the future.

PHARMACOTHERAPY IN ARDS

The pathogenesis of ARDS includes damage to the alveolar-capillary membrane, with leakage of protein-rich edema fluid into alveoli. This damage is propagated by a complex inflammatory response including but not limited to neutrophil activation, free-radical formation, dysregulation of the coagulation system, and extensive release of inflammatory mediators.^32,33 As a consequence, there are multiple potential targets for pharmacologic therapy in ARDS.

A variety of drugs, including corticosteroids, anti-inflammatory agents, immune-modulating agents, pulmonary vasodilators, antioxidants, and surfactants, have been studied in patients with ARDS.³⁴ But effective pharmacotherapy for ARDS remains extremely limited.

Neuromuscular blockade in early severe ARDS

Mechanical ventilation can result in injurious stretching of the lung parenchyma, either from alveolar overdistention (volutrauma) or from continual recruitment and derecruitment of unstable lung units during the ventilator cycle (atelectrauma).³⁵ Ventilator-induced lung injury can be exacerbated by asynchronous breathing.

In theory, neuromuscular blockers could minimize patient-ventilator asynchrony and provide much better control of tidal volume and pressure in patients with ARDS. This may result in less volutrauma and atelectrauma associated with asynchronous breathing. Data also suggest that cisatracurium (Nimbex), a neuromuscular blocking agent, may have a direct effect on the amount of inflammation in lungs with ARDS.³⁶

The ACURASYS study

The ARDS et Curarisation Systématique (ACURASYS) study³⁷ was a randomized trial in 340 patients undergoing mechanical ventilation for severe ARDS to evaluate the impact of neuromuscular blockade within the first 48 hours in this population.

The primary outcome was the mortality rate before hospital discharge or within 90 days of study entry. Secondary outcomes included the 28-day mortality rate, the rate of intensive care unit-acquired paresis, and the number of ventilator-free days. To be included, patients had to have been mechanically ventilated for less than 48 hours and to meet the AECC criteria for severe ARDS, with a PaO₂/FiO₂ ratio less than 150 mm Hg.

The intervention group received a continuous infusion of cisatracurium for 48 hours, while the control patients received placebo. Muscle strength was evaluated by clinical scoring of strength in different muscle groups.

Findings. The study groups were similar at baseline.

The crude 90-day mortality rate was lower in the cisatracurium group (31.6% vs 40.7%, P = .08). Regression analysis showed an improved 90-day survival rate with the use of this neuromuscular blocker after adjustment for severity of illness and the severity of ARDS (based on degree of hypoxemia and plateau pressures) (hazard ratio for death at 90 days 0.68; 95% CI 0.48–0.98; P = .04). The rate of paresis acquired in the intensive care unit did not differ significantly between the two groups.

Conclusion. In patients with severe ARDS, giving a neuromuscular blocking agent early improved the survival rate and increased the time off the ventilator without increasing muscle weakness.

These data are in line with similar findings from two other studies published by the same group.^38,39 A meta-analysis of 432 patients showed that the use of neuromuscular blockade in early severe ARDS is associated with a statistically significant effect on early mortality (relative risk 0.66, 95% CI 0.50–0.87).⁴⁰ The pooled analysis of these trials did not show any statistically significant critical-illness polyneuropathy.

These results need to be interpreted carefully, as we have inadequate data to see if they generalize to different intensive care units, and the evaluation and categorization of critical-illness polyneuropathy remains to be defined.

Cisatracurium is a promising treatment for moderate to severe ARDS and merits investigation in a large confirmatory randomized controlled trial.

Other pharmacologic agents

A number of other drugs have been studied in ARDS patients, including both inhaled and intravenous beta agonists,^41,42 statins,⁴³ and nutritional supplements.⁴⁴ But as with other drugs previously studied in ARDS such as corticosteroids, N-acetylcysteine, and surfactant,³⁴ these agents showed no effect on outcomes. In fact, a recent trial of intravenous salbutamol in ARDS patients was stopped after an interim analysis because of a higher incidence of arrhythmias and lactic acidosis with this agent.⁴²

These findings reaffirm that pharmacologic therapy needs to be carefully considered, and potential harms associated with these therapies need to be addressed before they are introduced in the care of critically ill patients.

Continued progress in understanding the pathophysiology of acute respiratory distress syndrome (ARDS) is translating into changes in the way we diagnose and manage it. Over the past 20 years, low tidal volume,¹ positive end-expiratory pressure (PEEP),² and fluid restriction³ have become the standard of care. A multidisciplinary approach, including targeted use of sedatives, early mobilization, and protocols for weaning from the ventilator, has also brought about substantial changes in ARDS management and its outcomes.^4–6

In this article, we review the most relevant articles about ARDS in the last 5 years. We include the new definition of ARDS and studies of ventilatory and nonventilatory therapies that have implications in managing patients with ARDS.

A STANDARDIZED APPROACH

ARDS is characterized by damage to the alveolar architecture, severe hypoxemia, and bilateral parenchymal opacities.

The working definition of ARDS developed in 1994 by the American-European Consensus Conference (AECC) was the basis for enrollment in most of the landmark trials and observational studies over the past 20 years.^7,8 However, it was limited in its reliability and validity.

An updated definition

In 2011, the ARDS Definition Task Force, using a novel consensus process, updated the ARDS definition,⁹ focusing on its feasibility, reliability, and validity in predicting response to therapies and outcomes in ARDS. This new “Berlin” definition is not substantially different from the old, but defines the criteria more specifically:

• Bilateral opacities, unexplained by nodules, atelectasis, or effusion, on chest radiography or computed tomography
• New or worsening respiratory symptoms, or a clinical insult associated with ARDS within 7 days of diagnosis
• Objective assessment of cardiac function (eg, with echocardiography) to exclude cardiogenic pulmonary edema
• Hypoxemia, with a partial pressure of arterial oxygen divided by the percentage of inspired oxygen (PaO₂/FiO₂ ratio) of 300 mm Hg or less despite noninvasive or invasive mechanical ventilation with PEEP or continuous positive airway pressure (CPAP) of at least 5 cm H₂O.

In addition, the new definition classifies the severity of disease on the basis of the degree of hypoxemia, ie, the PaO₂/FiO₂ ratio:

• Mild: PaO₂/FiO₂ ratio > 200 and ≤ 300 mm Hg
• Moderate: PaO₂/FiO₂ ratio > 100 and ≤ 200 mm Hg
• Severe: PaO₂/FiO₂ ratio ≤ 100 mm Hg.

The term “acute lung injury” has been eliminated, as has the previous criterion of a pulmonary artery wedge pressure of 18 mm Hg or less.

The panel also evaluated four ancillary variables for predicting outcomes in severe ARDS:

• Compliance of the respiratory system less than or equal to 40 mL/cm H₂O
• Radiographic severity (involvement of three or four quadrants on chest radiography)
• PEEP of 10 cm H₂O or greater
• Corrected expired volume 10 L/min or greater.

The task force evaluated the reliability and validity of this definition in a meta-analysis of 4,400 patients previously enrolled in randomized controlled trials or observational studies.

Findings. The Berlin definition predicted the risk of death better than the AECC definition. The mortality rate increased with the severity of ARDS, from 27% with mild disease to 32% with moderate disease to 45% with severe disease. The four ancillary variables did not contribute to the predictive validity of severe ARDS for mortality and were removed from the definition.

Thille et al¹⁰ retrospectively reviewed autopsy findings from 712 patients and found that the new definition identified a homogeneous group who had severe ARDS.¹⁰

Conclusions. The new definition may overcome some of the limitations of the old one, but it needs to be validated in clinical practice, especially its ability to predict death.

VENTILATORY SUPPORT

Prompt recognition, lung-protective ventilation, and a conservative fluid strategy remain the cornerstones of ARDS management. However, other strategies are being tested.

Prone-position ventilation in severe ARDS: The right therapy in a specific population

Prone-position ventilation was first described almost 30 years ago, but it has been used inconsistently in clinical practice.

Physiologic and observational studies indicated that prone positioning might improve survival in patients with ARDS, but several randomized trials failed to demonstrate any positive effect on outcomes.^11,12 Some trials also reported a higher rate of complications with this intervention.¹³ However, meta-analyses suggested that prone-position ventilation might have a beneficial effect in patients with severe ARDS (defined as a PaO₂/FiO₂ ratio ≤ 100 mm Hg).¹⁴

In view of these findings, investigators conducted a trial of prone-position ventilation exclusively in patients with severe ARDS.

The PROSEVA study

The Proning Severe ARDS Patients (PROSEVA) study was a randomized controlled trial designed to determine whether prone-position ventilation, applied early, would improve outcomes in patients with severe ARDS.¹⁵

In PROSEVA, 466 patients with severe ARDS (defined as a PaO₂/FiO₂ ratio < 150 mm Hg, FiO₂ ≥ 60%, and PEEP ≥ 5 cm H₂O) underwent either at least 16 hours of prone positioning or were left in the supine position after 12 to 24 hours of initial conventional mechanical ventilation. The patients were recruited from centers in France and Spain where prone-position ventilation had been used in daily practice for more than 5 years.

The primary outcome studied was the rate of death at 28 days. The secondary end points were the death rate at day 90, rates of successful extubation, the length of stay in the intensive care unit, and complications.

Findings. At study entry, the patients in the supine group were sicker, more of them required a vasopressor, and fewer of them were receiving neuromuscular blocking agents than those in the prone group. These baseline differences may have influenced the outcomes; the unadjusted 28-day mortality rate was 16.0% in the prone group compared with 32.8% in the supine group (P < .001). However, the hazard ratio for death with prone positioning was 0.39 (95% confidence interval [CI] 0.25–0.63) even after adjusting for severity and the use of vasopressors and neuromuscular blocking agents. Prone-position ventilation was not associated with a higher incidence of complications, and the rate of successful extubation was higher.

Conclusions. In patients with severe ARDS, early use of prolonged prone positioning significantly decreased the 28-day and 90-day mortality rates. This trial has made prone positioning one of the strategies in managing patients with early severe ARDS. To minimize complications such as pressure ulcers and line or tube dislodgement, personnel caring for these patients must follow a protocol and undergo specific training.

These results were corroborated by a meta-analysis by Beitler et al¹⁶ that found a significant decrease in mortality rate with prone-position ventilation even in older studies when lung-protective ventilation strategies were separated from high-tidal-volume ventilation.

High-frequency oscillatory ventilation: No benefit in two trials

Observational data and experimental studies suggested that high-frequency oscillatory ventilation (HFOV) is superior to conventional mechanical ventilation in ARDS patients.^17,18 However, outdated and cumbersome equipment, lack of protocols, and a lack of high-quality evidence led to limited and inconsistent use of HFOV, mainly as a rescue therapy in ARDS.¹⁹

Over the last few years, HFOV has been gaining acceptance, especially earlier in the course of ARDS.²⁰ After preliminary clinical trials reported promising results, two trials conducted in Canada and the United Kingdom compared HFOV vs conventional mechanical ventilation in patients with ARDS.

The OSCAR study

The Oscillation in ARDS (OSCAR) study²¹ was a “pragmatic” trial²² (ie, it had minimal exclusion criteria) of the safety and effectiveness of HFOV as a primary ventilatory strategy for ARDS. It included 795 patients randomized to receive conventional ventilation (n = 397) or HFOV (n = 398). Research centers followed detailed algorithms for HFOV management and adopted their usual practice for conventional ventilation. Medical care was given according to the clinician’s judgment.

The primary outcome studied was survival at 30 days. The secondary outcomes were all-cause mortality in the intensive care unit and the hospital, duration of mechanical ventilation, and use of antimicrobial, sedative, vasoactive, and neuromuscular-blocking drugs.

Findings. The patient baseline characteristics were similar in both groups.

There was no significant difference in intensive care unit mortality rates, hospital mortality rates, or mortality rates at 30 days (41.7% in the HFOV group vs 41.1% in the conventional ventilation group; P = .85, 95% CI 6.1–7.5) even after adjustments for center or severity of illness.

The duration of mechanical ventilation was similar in both groups (14.9 ± 13.3 days in the HFOV group vs 14.1 ± 13.4 days in the conventional ventilation group, P = .41). However, sedatives and neuromuscular-blocking drugs were used more often and longer in the HFOV group than in the conventional ventilation group. There was no difference in the use of vasoactive or antimicrobial medications.

Conclusions. This multicenter randomized control trial did not demonstrate any benefit from using HFOV for routine management of ARDS. Its pragmatic design made it less likely to reach a firm conclusion,²² but it at least made a case against routinely using HFOV in patients with ARDS.

The OSCILLATE study

The Oscillation for Acute Respiratory Distress Syndrome Treated Early (OSCILLATE) study²³ assessed the safety and efficacy of HFOV as a treatment for early-onset moderate-to-severe ARDS.

The inclusion criteria were similar to those in the OSCAR trial except that pulmonary symptoms had to be present less than 2 weeks and ARDS assessment was done under standard ventilator settings. As this was an efficacy trial, it had more exclusion criteria than the OSCAR trial. A total of 548 patients were randomized to receive conventional ventilation (n = 273) or HFOV (n = 275). The baseline characteristics were similar between groups.

Conventional ventilation was given according to a protocol used in an earlier trial² and included recruitment maneuvers. HFOV was given in centers that had experience in this treatment, and there were protocols for ventilation management, hemodynamic optimization, and weaning. All other care was left to the clinician’s choice.

The primary outcome studied was in-hospital mortality. The investigators also evaluated whether there were interactions between the treatment and baseline severity of lung injury and center experience with HFOV.

Findings. The trial was stopped after an interim analysis found that HFOV might be harmful, although the statistical threshold for stopping was not reached. The in-hospital mortality rate was 47% in the HFOV group and 35% in the control group (relative risk of death with HFOV 1.33, 95% CI 1.09–1.64, P = .005). HFOV was worse than conventional ventilation regardless of the severity of disease or center experience. The HFOV group had higher mean airway pressures but similar FiO₂ compared with the conventional ventilation group.

The HFOV group received significantly more vasopressors, sedatives, and neuromuscular blockers. This group’s fluid balance was higher as well, but not significantly so. Refractory hypoxemia (defined as PaO₂ < 60 mm Hg for 1 hour with an FiO₂ of 1.0 and neuromuscular blockade) was more frequent in the conventional ventilation group, but the number of deaths in the subgroup with refractory hypoxemia was similar with either treatment.

Conclusions. This multicenter randomized controlled trial demonstrated that HFOV was harmful when used routinely to manage ARDS. The trial’s protocol was based on the results of a pilot study carried out by the same investigators, which provided the best evidence available regarding the safety of HFOV at that time.

The results of the OSCAR and OSCILLATE trials have quelled enthusiasm for early, routine use of HFOV in ARDS. Although there are concerns that the protocol (ie, the way HFOV was implemented) rather than HFOV itself may have led to worse outcomes, there is no signal to support its routine use. We need further studies to define if it remains a viable rescue therapy.

Extracorporeal membrane oxygenation: Is it a viable option in severe ARDS?

Extracorporeal membrane oxygenation (ECMO) uses cardiopulmonary bypass technology to provide gas exchange. In patients with severe hypoxemia, ECMO can ensure adequate oxygenation and ventilation while ensuring the optimization of lung-protective ventilation. But ECMO was never as successful in adults with ARDS as it was in children and neonates.²⁴

The first two trials of ECMO in ARDS^24,25 reported equal or worse survival rates compared with conventional ventilation, and the overall mortality rate in these studies was staggeringly high. However, these studies were carried out before the era of lung-protective ventilation and at a time when ECMO technology was relatively primitive.

With new technology such as venovenous circuits and smaller cannulas, ECMO has gained more acceptance. It was used in patients with severe or refractory hypoxemia associated with ARDS during the H1N1 pandemic.^26,27

The CESAR trial

The Conventional Ventilatory Support Versus Extracorporeal Membrane Oxygenation for Severe Adult Respiratory Failure (CESAR) trial²⁸ assessed the safety, clinical efficacy, and cost-effectiveness of ECMO in managing severe ARDS. It compared best standard practice vs a protocol that included ECMO. The trial was conducted from 2001 to 2006.

Patients with severe ARDS, as defined by a Murray score²⁹ greater than 3 or uncompensated hypercapnea, were prospectively randomized and recruited from an ECMO center and 148 tertiary intensive care units and referral hospitals in England. This was a pragmatic trial, with minimal exclusion criteria (essentially, mechanical ventilation with high pressures and high FiO₂ for more than 7 days, intracranial bleeding, or contraindication to heparinization).

A total of 180 patients were randomized in a one-to-one ratio to receive ECMO or conventional management. The ventilator management in the conventional treatment group was not done according to a protocol but in general was low-volume and low-pressure. All patients randomized to ECMO were transferred to the ECMO center and treated according to a standardized ventilation protocol. After 12 hours, if predefined goals were not reached, venovenous ECMO was started. Patients assigned to conventional management could not cross over to ECMO.

The primary outcomes were death or severe disability at 6 months after randomization, and cost-effectiveness. The secondary outcomes were hospital resource use (eg, rescue techniques, length of stay, duration of ECMO) and health status after 6 months.

Findings. The groups were similar at baseline. Sixty-eight (75%) of the 90 patients randomized to receive ECMO actually received it. Of the 22 patients who did not receive ECMO, 16 (18% of the 90) improved on conventional therapy, 5 (6%) died during or before transfer, and 1 could not receive heparin.

Two patients had severe complications in the ECMO group: one had an arterial puncture, and one had an oxygen delivery failure during transport. In each case, these events contributed to the death of the patient.

More patients in the ECMO group received lung-protective ventilation, 84 (93%) vs 63 (70%).

The primary outcome, ie, death or severe disability at 6 months, occurred in 33 (37%) of the 90 patients in the ECMO group and in 46 (53%) of the patients in the conventional management group (relative risk 0.69, 95% CI 0.05–0.97, P = .03). More patients in the ECMO group survived, but the difference was not statistically significant (relative risk of death 0.73, 95% CI 0.52–1.03, P = .07). The most common cause of death in the ECMO group was multiorgan failure (42%), whereas in the conventional management group, the most common cause of death was respiratory failure (60%).

Length of stay in the hospital and in the critical care unit and health care costs were double for patients in the ECMO group. There was no difference in quality-of-life markers at 6 months in the survivors.

Conclusions. This pragmatic trial demonstrated that a protocol that includes ECMO could improve survival rates in ARDS.

Of note, the ECMO group got care in regional centers that used protocols. Therefore, in interpreting the results of this trial, we have to consider that being in a center with protocol-specified care for ARDS could drive some of the difference in mortality rates.

Regardless, this trial demonstrated that ECMO is feasible and led to better outcomes than expected. The findings were encouraging, and spurred the use of ECMO in severe ARDS during the 2009 H1N1 pandemic. Two propensity-matched studies and a number of case series reported a survival benefit associated with the use of ECMO in patients with severe ARDS.^27,30

A recent meta-analysis also reported that ECMO might lower the mortality rate in ARDS; however, the patients in the H1N1 pandemic were younger and usually had isolated respiratory failure.³¹

The success of ECMO has opened new possibilities in the management of ARDS. As the technology improves and our experience increases, ECMO will likely gain more acceptance as a treatment for severe ARDS.

Airway pressure release ventilation

The use of airway pressure release ventilation and other ventilator modalities in ARDS is not supported by current evidence, though results of clinical trials may influence our practice in the future.

PHARMACOTHERAPY IN ARDS

The pathogenesis of ARDS includes damage to the alveolar-capillary membrane, with leakage of protein-rich edema fluid into alveoli. This damage is propagated by a complex inflammatory response including but not limited to neutrophil activation, free-radical formation, dysregulation of the coagulation system, and extensive release of inflammatory mediators.^32,33 As a consequence, there are multiple potential targets for pharmacologic therapy in ARDS.

A variety of drugs, including corticosteroids, anti-inflammatory agents, immune-modulating agents, pulmonary vasodilators, antioxidants, and surfactants, have been studied in patients with ARDS.³⁴ But effective pharmacotherapy for ARDS remains extremely limited.

Neuromuscular blockade in early severe ARDS

Mechanical ventilation can result in injurious stretching of the lung parenchyma, either from alveolar overdistention (volutrauma) or from continual recruitment and derecruitment of unstable lung units during the ventilator cycle (atelectrauma).³⁵ Ventilator-induced lung injury can be exacerbated by asynchronous breathing.

In theory, neuromuscular blockers could minimize patient-ventilator asynchrony and provide much better control of tidal volume and pressure in patients with ARDS. This may result in less volutrauma and atelectrauma associated with asynchronous breathing. Data also suggest that cisatracurium (Nimbex), a neuromuscular blocking agent, may have a direct effect on the amount of inflammation in lungs with ARDS.³⁶

The ACURASYS study

The ARDS et Curarisation Systématique (ACURASYS) study³⁷ was a randomized trial in 340 patients undergoing mechanical ventilation for severe ARDS to evaluate the impact of neuromuscular blockade within the first 48 hours in this population.

The primary outcome was the mortality rate before hospital discharge or within 90 days of study entry. Secondary outcomes included the 28-day mortality rate, the rate of intensive care unit-acquired paresis, and the number of ventilator-free days. To be included, patients had to have been mechanically ventilated for less than 48 hours and to meet the AECC criteria for severe ARDS, with a PaO₂/FiO₂ ratio less than 150 mm Hg.

The intervention group received a continuous infusion of cisatracurium for 48 hours, while the control patients received placebo. Muscle strength was evaluated by clinical scoring of strength in different muscle groups.

Findings. The study groups were similar at baseline.

The crude 90-day mortality rate was lower in the cisatracurium group (31.6% vs 40.7%, P = .08). Regression analysis showed an improved 90-day survival rate with the use of this neuromuscular blocker after adjustment for severity of illness and the severity of ARDS (based on degree of hypoxemia and plateau pressures) (hazard ratio for death at 90 days 0.68; 95% CI 0.48–0.98; P = .04). The rate of paresis acquired in the intensive care unit did not differ significantly between the two groups.

Conclusion. In patients with severe ARDS, giving a neuromuscular blocking agent early improved the survival rate and increased the time off the ventilator without increasing muscle weakness.

These data are in line with similar findings from two other studies published by the same group.^38,39 A meta-analysis of 432 patients showed that the use of neuromuscular blockade in early severe ARDS is associated with a statistically significant effect on early mortality (relative risk 0.66, 95% CI 0.50–0.87).⁴⁰ The pooled analysis of these trials did not show any statistically significant critical-illness polyneuropathy.

These results need to be interpreted carefully, as we have inadequate data to see if they generalize to different intensive care units, and the evaluation and categorization of critical-illness polyneuropathy remains to be defined.

Cisatracurium is a promising treatment for moderate to severe ARDS and merits investigation in a large confirmatory randomized controlled trial.

Other pharmacologic agents

A number of other drugs have been studied in ARDS patients, including both inhaled and intravenous beta agonists,^41,42 statins,⁴³ and nutritional supplements.⁴⁴ But as with other drugs previously studied in ARDS such as corticosteroids, N-acetylcysteine, and surfactant,³⁴ these agents showed no effect on outcomes. In fact, a recent trial of intravenous salbutamol in ARDS patients was stopped after an interim analysis because of a higher incidence of arrhythmias and lactic acidosis with this agent.⁴²

These findings reaffirm that pharmacologic therapy needs to be carefully considered, and potential harms associated with these therapies need to be addressed before they are introduced in the care of critically ill patients.

Continued progress in understanding the pathophysiology of acute respiratory distress syndrome (ARDS) is translating into changes in the way we diagnose and manage it. Over the past 20 years, low tidal volume,¹ positive end-expiratory pressure (PEEP),² and fluid restriction³ have become the standard of care. A multidisciplinary approach, including targeted use of sedatives, early mobilization, and protocols for weaning from the ventilator, has also brought about substantial changes in ARDS management and its outcomes.^4–6

In this article, we review the most relevant articles about ARDS in the last 5 years. We include the new definition of ARDS and studies of ventilatory and nonventilatory therapies that have implications in managing patients with ARDS.

A STANDARDIZED APPROACH

ARDS is characterized by damage to the alveolar architecture, severe hypoxemia, and bilateral parenchymal opacities.

The working definition of ARDS developed in 1994 by the American-European Consensus Conference (AECC) was the basis for enrollment in most of the landmark trials and observational studies over the past 20 years.^7,8 However, it was limited in its reliability and validity.

An updated definition

In 2011, the ARDS Definition Task Force, using a novel consensus process, updated the ARDS definition,⁹ focusing on its feasibility, reliability, and validity in predicting response to therapies and outcomes in ARDS. This new “Berlin” definition is not substantially different from the old, but defines the criteria more specifically:

• Bilateral opacities, unexplained by nodules, atelectasis, or effusion, on chest radiography or computed tomography
• New or worsening respiratory symptoms, or a clinical insult associated with ARDS within 7 days of diagnosis
• Objective assessment of cardiac function (eg, with echocardiography) to exclude cardiogenic pulmonary edema
• Hypoxemia, with a partial pressure of arterial oxygen divided by the percentage of inspired oxygen (PaO₂/FiO₂ ratio) of 300 mm Hg or less despite noninvasive or invasive mechanical ventilation with PEEP or continuous positive airway pressure (CPAP) of at least 5 cm H₂O.

In addition, the new definition classifies the severity of disease on the basis of the degree of hypoxemia, ie, the PaO₂/FiO₂ ratio:

• Mild: PaO₂/FiO₂ ratio > 200 and ≤ 300 mm Hg
• Moderate: PaO₂/FiO₂ ratio > 100 and ≤ 200 mm Hg
• Severe: PaO₂/FiO₂ ratio ≤ 100 mm Hg.

The term “acute lung injury” has been eliminated, as has the previous criterion of a pulmonary artery wedge pressure of 18 mm Hg or less.

The panel also evaluated four ancillary variables for predicting outcomes in severe ARDS:

• Compliance of the respiratory system less than or equal to 40 mL/cm H₂O
• Radiographic severity (involvement of three or four quadrants on chest radiography)
• PEEP of 10 cm H₂O or greater
• Corrected expired volume 10 L/min or greater.

The task force evaluated the reliability and validity of this definition in a meta-analysis of 4,400 patients previously enrolled in randomized controlled trials or observational studies.

Findings. The Berlin definition predicted the risk of death better than the AECC definition. The mortality rate increased with the severity of ARDS, from 27% with mild disease to 32% with moderate disease to 45% with severe disease. The four ancillary variables did not contribute to the predictive validity of severe ARDS for mortality and were removed from the definition.

Thille et al¹⁰ retrospectively reviewed autopsy findings from 712 patients and found that the new definition identified a homogeneous group who had severe ARDS.¹⁰

Conclusions. The new definition may overcome some of the limitations of the old one, but it needs to be validated in clinical practice, especially its ability to predict death.

VENTILATORY SUPPORT

Prompt recognition, lung-protective ventilation, and a conservative fluid strategy remain the cornerstones of ARDS management. However, other strategies are being tested.

Prone-position ventilation in severe ARDS: The right therapy in a specific population

Prone-position ventilation was first described almost 30 years ago, but it has been used inconsistently in clinical practice.

Physiologic and observational studies indicated that prone positioning might improve survival in patients with ARDS, but several randomized trials failed to demonstrate any positive effect on outcomes.^11,12 Some trials also reported a higher rate of complications with this intervention.¹³ However, meta-analyses suggested that prone-position ventilation might have a beneficial effect in patients with severe ARDS (defined as a PaO₂/FiO₂ ratio ≤ 100 mm Hg).¹⁴

In view of these findings, investigators conducted a trial of prone-position ventilation exclusively in patients with severe ARDS.

The PROSEVA study

The Proning Severe ARDS Patients (PROSEVA) study was a randomized controlled trial designed to determine whether prone-position ventilation, applied early, would improve outcomes in patients with severe ARDS.¹⁵

In PROSEVA, 466 patients with severe ARDS (defined as a PaO₂/FiO₂ ratio < 150 mm Hg, FiO₂ ≥ 60%, and PEEP ≥ 5 cm H₂O) underwent either at least 16 hours of prone positioning or were left in the supine position after 12 to 24 hours of initial conventional mechanical ventilation. The patients were recruited from centers in France and Spain where prone-position ventilation had been used in daily practice for more than 5 years.

The primary outcome studied was the rate of death at 28 days. The secondary end points were the death rate at day 90, rates of successful extubation, the length of stay in the intensive care unit, and complications.

Findings. At study entry, the patients in the supine group were sicker, more of them required a vasopressor, and fewer of them were receiving neuromuscular blocking agents than those in the prone group. These baseline differences may have influenced the outcomes; the unadjusted 28-day mortality rate was 16.0% in the prone group compared with 32.8% in the supine group (P < .001). However, the hazard ratio for death with prone positioning was 0.39 (95% confidence interval [CI] 0.25–0.63) even after adjusting for severity and the use of vasopressors and neuromuscular blocking agents. Prone-position ventilation was not associated with a higher incidence of complications, and the rate of successful extubation was higher.

Conclusions. In patients with severe ARDS, early use of prolonged prone positioning significantly decreased the 28-day and 90-day mortality rates. This trial has made prone positioning one of the strategies in managing patients with early severe ARDS. To minimize complications such as pressure ulcers and line or tube dislodgement, personnel caring for these patients must follow a protocol and undergo specific training.

These results were corroborated by a meta-analysis by Beitler et al¹⁶ that found a significant decrease in mortality rate with prone-position ventilation even in older studies when lung-protective ventilation strategies were separated from high-tidal-volume ventilation.

High-frequency oscillatory ventilation: No benefit in two trials

Observational data and experimental studies suggested that high-frequency oscillatory ventilation (HFOV) is superior to conventional mechanical ventilation in ARDS patients.^17,18 However, outdated and cumbersome equipment, lack of protocols, and a lack of high-quality evidence led to limited and inconsistent use of HFOV, mainly as a rescue therapy in ARDS.¹⁹

Over the last few years, HFOV has been gaining acceptance, especially earlier in the course of ARDS.²⁰ After preliminary clinical trials reported promising results, two trials conducted in Canada and the United Kingdom compared HFOV vs conventional mechanical ventilation in patients with ARDS.

The OSCAR study

The Oscillation in ARDS (OSCAR) study²¹ was a “pragmatic” trial²² (ie, it had minimal exclusion criteria) of the safety and effectiveness of HFOV as a primary ventilatory strategy for ARDS. It included 795 patients randomized to receive conventional ventilation (n = 397) or HFOV (n = 398). Research centers followed detailed algorithms for HFOV management and adopted their usual practice for conventional ventilation. Medical care was given according to the clinician’s judgment.

The primary outcome studied was survival at 30 days. The secondary outcomes were all-cause mortality in the intensive care unit and the hospital, duration of mechanical ventilation, and use of antimicrobial, sedative, vasoactive, and neuromuscular-blocking drugs.

Findings. The patient baseline characteristics were similar in both groups.

There was no significant difference in intensive care unit mortality rates, hospital mortality rates, or mortality rates at 30 days (41.7% in the HFOV group vs 41.1% in the conventional ventilation group; P = .85, 95% CI 6.1–7.5) even after adjustments for center or severity of illness.

The duration of mechanical ventilation was similar in both groups (14.9 ± 13.3 days in the HFOV group vs 14.1 ± 13.4 days in the conventional ventilation group, P = .41). However, sedatives and neuromuscular-blocking drugs were used more often and longer in the HFOV group than in the conventional ventilation group. There was no difference in the use of vasoactive or antimicrobial medications.

Conclusions. This multicenter randomized control trial did not demonstrate any benefit from using HFOV for routine management of ARDS. Its pragmatic design made it less likely to reach a firm conclusion,²² but it at least made a case against routinely using HFOV in patients with ARDS.

The OSCILLATE study

The Oscillation for Acute Respiratory Distress Syndrome Treated Early (OSCILLATE) study²³ assessed the safety and efficacy of HFOV as a treatment for early-onset moderate-to-severe ARDS.

The inclusion criteria were similar to those in the OSCAR trial except that pulmonary symptoms had to be present less than 2 weeks and ARDS assessment was done under standard ventilator settings. As this was an efficacy trial, it had more exclusion criteria than the OSCAR trial. A total of 548 patients were randomized to receive conventional ventilation (n = 273) or HFOV (n = 275). The baseline characteristics were similar between groups.

Conventional ventilation was given according to a protocol used in an earlier trial² and included recruitment maneuvers. HFOV was given in centers that had experience in this treatment, and there were protocols for ventilation management, hemodynamic optimization, and weaning. All other care was left to the clinician’s choice.

The primary outcome studied was in-hospital mortality. The investigators also evaluated whether there were interactions between the treatment and baseline severity of lung injury and center experience with HFOV.

Findings. The trial was stopped after an interim analysis found that HFOV might be harmful, although the statistical threshold for stopping was not reached. The in-hospital mortality rate was 47% in the HFOV group and 35% in the control group (relative risk of death with HFOV 1.33, 95% CI 1.09–1.64, P = .005). HFOV was worse than conventional ventilation regardless of the severity of disease or center experience. The HFOV group had higher mean airway pressures but similar FiO₂ compared with the conventional ventilation group.

The HFOV group received significantly more vasopressors, sedatives, and neuromuscular blockers. This group’s fluid balance was higher as well, but not significantly so. Refractory hypoxemia (defined as PaO₂ < 60 mm Hg for 1 hour with an FiO₂ of 1.0 and neuromuscular blockade) was more frequent in the conventional ventilation group, but the number of deaths in the subgroup with refractory hypoxemia was similar with either treatment.

Conclusions. This multicenter randomized controlled trial demonstrated that HFOV was harmful when used routinely to manage ARDS. The trial’s protocol was based on the results of a pilot study carried out by the same investigators, which provided the best evidence available regarding the safety of HFOV at that time.

The results of the OSCAR and OSCILLATE trials have quelled enthusiasm for early, routine use of HFOV in ARDS. Although there are concerns that the protocol (ie, the way HFOV was implemented) rather than HFOV itself may have led to worse outcomes, there is no signal to support its routine use. We need further studies to define if it remains a viable rescue therapy.

Extracorporeal membrane oxygenation: Is it a viable option in severe ARDS?

Extracorporeal membrane oxygenation (ECMO) uses cardiopulmonary bypass technology to provide gas exchange. In patients with severe hypoxemia, ECMO can ensure adequate oxygenation and ventilation while ensuring the optimization of lung-protective ventilation. But ECMO was never as successful in adults with ARDS as it was in children and neonates.²⁴

The first two trials of ECMO in ARDS^24,25 reported equal or worse survival rates compared with conventional ventilation, and the overall mortality rate in these studies was staggeringly high. However, these studies were carried out before the era of lung-protective ventilation and at a time when ECMO technology was relatively primitive.

With new technology such as venovenous circuits and smaller cannulas, ECMO has gained more acceptance. It was used in patients with severe or refractory hypoxemia associated with ARDS during the H1N1 pandemic.^26,27

The CESAR trial

The Conventional Ventilatory Support Versus Extracorporeal Membrane Oxygenation for Severe Adult Respiratory Failure (CESAR) trial²⁸ assessed the safety, clinical efficacy, and cost-effectiveness of ECMO in managing severe ARDS. It compared best standard practice vs a protocol that included ECMO. The trial was conducted from 2001 to 2006.

Patients with severe ARDS, as defined by a Murray score²⁹ greater than 3 or uncompensated hypercapnea, were prospectively randomized and recruited from an ECMO center and 148 tertiary intensive care units and referral hospitals in England. This was a pragmatic trial, with minimal exclusion criteria (essentially, mechanical ventilation with high pressures and high FiO₂ for more than 7 days, intracranial bleeding, or contraindication to heparinization).

A total of 180 patients were randomized in a one-to-one ratio to receive ECMO or conventional management. The ventilator management in the conventional treatment group was not done according to a protocol but in general was low-volume and low-pressure. All patients randomized to ECMO were transferred to the ECMO center and treated according to a standardized ventilation protocol. After 12 hours, if predefined goals were not reached, venovenous ECMO was started. Patients assigned to conventional management could not cross over to ECMO.

The primary outcomes were death or severe disability at 6 months after randomization, and cost-effectiveness. The secondary outcomes were hospital resource use (eg, rescue techniques, length of stay, duration of ECMO) and health status after 6 months.

Findings. The groups were similar at baseline. Sixty-eight (75%) of the 90 patients randomized to receive ECMO actually received it. Of the 22 patients who did not receive ECMO, 16 (18% of the 90) improved on conventional therapy, 5 (6%) died during or before transfer, and 1 could not receive heparin.

Two patients had severe complications in the ECMO group: one had an arterial puncture, and one had an oxygen delivery failure during transport. In each case, these events contributed to the death of the patient.

More patients in the ECMO group received lung-protective ventilation, 84 (93%) vs 63 (70%).

The primary outcome, ie, death or severe disability at 6 months, occurred in 33 (37%) of the 90 patients in the ECMO group and in 46 (53%) of the patients in the conventional management group (relative risk 0.69, 95% CI 0.05–0.97, P = .03). More patients in the ECMO group survived, but the difference was not statistically significant (relative risk of death 0.73, 95% CI 0.52–1.03, P = .07). The most common cause of death in the ECMO group was multiorgan failure (42%), whereas in the conventional management group, the most common cause of death was respiratory failure (60%).

Length of stay in the hospital and in the critical care unit and health care costs were double for patients in the ECMO group. There was no difference in quality-of-life markers at 6 months in the survivors.

Conclusions. This pragmatic trial demonstrated that a protocol that includes ECMO could improve survival rates in ARDS.

Of note, the ECMO group got care in regional centers that used protocols. Therefore, in interpreting the results of this trial, we have to consider that being in a center with protocol-specified care for ARDS could drive some of the difference in mortality rates.

Regardless, this trial demonstrated that ECMO is feasible and led to better outcomes than expected. The findings were encouraging, and spurred the use of ECMO in severe ARDS during the 2009 H1N1 pandemic. Two propensity-matched studies and a number of case series reported a survival benefit associated with the use of ECMO in patients with severe ARDS.^27,30

A recent meta-analysis also reported that ECMO might lower the mortality rate in ARDS; however, the patients in the H1N1 pandemic were younger and usually had isolated respiratory failure.³¹

The success of ECMO has opened new possibilities in the management of ARDS. As the technology improves and our experience increases, ECMO will likely gain more acceptance as a treatment for severe ARDS.

Airway pressure release ventilation

The use of airway pressure release ventilation and other ventilator modalities in ARDS is not supported by current evidence, though results of clinical trials may influence our practice in the future.

PHARMACOTHERAPY IN ARDS

The pathogenesis of ARDS includes damage to the alveolar-capillary membrane, with leakage of protein-rich edema fluid into alveoli. This damage is propagated by a complex inflammatory response including but not limited to neutrophil activation, free-radical formation, dysregulation of the coagulation system, and extensive release of inflammatory mediators.^32,33 As a consequence, there are multiple potential targets for pharmacologic therapy in ARDS.

A variety of drugs, including corticosteroids, anti-inflammatory agents, immune-modulating agents, pulmonary vasodilators, antioxidants, and surfactants, have been studied in patients with ARDS.³⁴ But effective pharmacotherapy for ARDS remains extremely limited.

Neuromuscular blockade in early severe ARDS

Mechanical ventilation can result in injurious stretching of the lung parenchyma, either from alveolar overdistention (volutrauma) or from continual recruitment and derecruitment of unstable lung units during the ventilator cycle (atelectrauma).³⁵ Ventilator-induced lung injury can be exacerbated by asynchronous breathing.

In theory, neuromuscular blockers could minimize patient-ventilator asynchrony and provide much better control of tidal volume and pressure in patients with ARDS. This may result in less volutrauma and atelectrauma associated with asynchronous breathing. Data also suggest that cisatracurium (Nimbex), a neuromuscular blocking agent, may have a direct effect on the amount of inflammation in lungs with ARDS.³⁶

The ACURASYS study

The ARDS et Curarisation Systématique (ACURASYS) study³⁷ was a randomized trial in 340 patients undergoing mechanical ventilation for severe ARDS to evaluate the impact of neuromuscular blockade within the first 48 hours in this population.

The primary outcome was the mortality rate before hospital discharge or within 90 days of study entry. Secondary outcomes included the 28-day mortality rate, the rate of intensive care unit-acquired paresis, and the number of ventilator-free days. To be included, patients had to have been mechanically ventilated for less than 48 hours and to meet the AECC criteria for severe ARDS, with a PaO₂/FiO₂ ratio less than 150 mm Hg.

The intervention group received a continuous infusion of cisatracurium for 48 hours, while the control patients received placebo. Muscle strength was evaluated by clinical scoring of strength in different muscle groups.

Findings. The study groups were similar at baseline.

The crude 90-day mortality rate was lower in the cisatracurium group (31.6% vs 40.7%, P = .08). Regression analysis showed an improved 90-day survival rate with the use of this neuromuscular blocker after adjustment for severity of illness and the severity of ARDS (based on degree of hypoxemia and plateau pressures) (hazard ratio for death at 90 days 0.68; 95% CI 0.48–0.98; P = .04). The rate of paresis acquired in the intensive care unit did not differ significantly between the two groups.

Conclusion. In patients with severe ARDS, giving a neuromuscular blocking agent early improved the survival rate and increased the time off the ventilator without increasing muscle weakness.

These data are in line with similar findings from two other studies published by the same group.^38,39 A meta-analysis of 432 patients showed that the use of neuromuscular blockade in early severe ARDS is associated with a statistically significant effect on early mortality (relative risk 0.66, 95% CI 0.50–0.87).⁴⁰ The pooled analysis of these trials did not show any statistically significant critical-illness polyneuropathy.

These results need to be interpreted carefully, as we have inadequate data to see if they generalize to different intensive care units, and the evaluation and categorization of critical-illness polyneuropathy remains to be defined.

Cisatracurium is a promising treatment for moderate to severe ARDS and merits investigation in a large confirmatory randomized controlled trial.

Other pharmacologic agents

A number of other drugs have been studied in ARDS patients, including both inhaled and intravenous beta agonists,^41,42 statins,⁴³ and nutritional supplements.⁴⁴ But as with other drugs previously studied in ARDS such as corticosteroids, N-acetylcysteine, and surfactant,³⁴ these agents showed no effect on outcomes. In fact, a recent trial of intravenous salbutamol in ARDS patients was stopped after an interim analysis because of a higher incidence of arrhythmias and lactic acidosis with this agent.⁴²

These findings reaffirm that pharmacologic therapy needs to be carefully considered, and potential harms associated with these therapies need to be addressed before they are introduced in the care of critically ill patients.

A 61-year-old man with type 2 diabetes mellitus on glimepiride therapy presented with somnolence and slurred speech. His capillary glucose level was 17 mg/dL and his serum glucose level was 28 mg/dL. He was treated with intravenous dextrose, and his glucose level promptly returned to normal.

He had been adherent to his medication regimen and denied overmedicating or accidental overdosing. Over the past 7 months, he had noted redness on his palms, a rash on his legs, intermittent moderate to severe headaches, weight loss, and decreased appetite. In addition, his blood pressure had been labile, which his physicians had attributed to autonomic instability. He had continued on the same dose of glimepiride despite losing weight.

His history included multivessel coronary artery disease treated with angioplasty and placement of multiple coronary stents; ischemic cardiomyopathy with a left ventricular ejection fraction of 28%; implantation of a cardioverter-defibrillator for secondary prevention of ventricular arrhythmia; an ischemic stroke; and multiple sclerosis complicated by bilateral blindness, with optic nerve involvement and autonomic instability, present for over a year and manifested by labile blood pressure. He was a long-time tobacco user. His daily medications included ticagrelor 90 mg, aspirin 81 mg, metoprolol 50 mg, ramipril 10 mg, simvastatin 20 mg, glimepiride 2 mg, and esomeprazole 40 mg. He needed help taking his medications.

At the time of hospital admission, his heart rate was 69 beats per minute with a regular rhythm, blood pressure 115/73 mm Hg, respiratory rate 11 breaths per minute with an oxygen saturation of 99% on room air, and oral temperature 34.7°C (94.5°F). He appeared to be in no distress.

Cardiovascular examination revealed no murmurs or gallops; there was mild nonpitting edema of the lower extremities. Pulmonary, abdominal, and neurologic examinations were unrevealing except for bilateral blindness. Vascular examination revealed no bruits. Results of a complete blood cell count and metabolic panel were normal except for a hemoglobin level of 9.9 g/dL (reference range 13.5–17.5) and a platelet count of 477 × 10⁹/L (150–450).

Although he continued to receive the same medications he had been taking at home, his blood pressure fluctuated. On the second hospital day, it reached 186/135 mm Hg, at which time he also had palpitations, dyspnea, and crackles in the lower lobes of both lungs. Volume resuscitation on admission was suspected to have played a role, and he received furosemide, which improved his symptoms. But several hours later, his blood pressure rose again, and he became diaphoretic. Despite aggressive treatment with different antihypertensive agents, his blood pressure remained high and his symptoms persisted. Chest radiography showed no evidence of pulmonary edema. Because of his progressive dyspnea, the diagnosis of pulmonary embolism was entertained.

CAUSES OF RESISTANT HYPERTENSION

1. What could explain this patient’s high blood pressure?

• A drug effect
• Renovascular disease
• Excess circulating catecholamines
• Obstructive sleep apnea
• Primary aldosteronism

Sympathomimetic drugs such as epinephrine, norepinephrine, dopamine, and vasopressin, which are used when hemodynamic support is required, can raise both systolic and diastolic blood pressure. Nonsteroidal anti-inflammatory drugs and nasal decongestants are common culprits in the community. However, our patient was using none of these drugs.

Renovascular disease is one of many causes of resistant hypertension, accounting for 8% of all cases.^1,2 Despite fluctuations, the blood pressure often remains chronically elevated, its changes are less paroxysmal than in our patient, and a precipitating factor such as a dietary indiscretion is sometimes identified.¹

Excess circulating catecholamines can be a result of stress, exogenous administration, or endogenous oversecretion. Our patient’s clinical presentation is highly suspicious for a high-catecholamine state, and this should be further evaluated.

Obstructive sleep apnea is common in patients with resistant hypertension, with an estimated prevalence as high as 60% in this group.^3,4

Primary aldosteronism has an estimated prevalence of about 20% in patients evaluated for resistant hypertension.⁵

AN ADRENAL MASS IS INCIDENTALLY DISCOVERED

Computed tomographic angiography of the chest revealed no evidence of pulmonary emboli. There was mild dilation of the central pulmonary arteries and an incidental, incompletely imaged 4.7-by-3.4-cm mass of mixed attenuation in the right adrenal gland, with macroscopic fat within the lesion.

Computed tomography (CT) of the abdomen with dedicated cuts through the adrenal glands revealed a 4.7-cm heterogeneous right adrenal mass with a density of 34 Hounsfield units (HU). The left adrenal gland appeared diffusely enlarged without a discretely seen mass, consistent with hyperplasticity (Figure 1).

2. Based on the patient’s clinical presentation and findings on CT, what would be the most likely diagnosis for this incidentally found adrenal mass?

• Adrenocortical adenoma
• Adrenocortical carcinoma
• Metastatic mass
• Pheochromocytoma

Adrenocortical adenoma can present as a small homogeneous mass of variable size, with smooth margins, and rarely containing hemorrhagic tissue or calcifications. The typical density on nonenhanced CT is less than 10 HU. On enhanced CT, it is nonvascular. T2-weighted magnetic resonance imaging (MRI) shows a lesion of the same intensity as liver tissue.⁶

Adrenocortical adenoma is not classically associated with autologous activity and thus is less likely to explain our patient’s symptoms.

Adrenocortical carcinoma can present as a large heterogeneous mass, usually greater than 4 cm in diameter, with irregular margins and areas of necrosis, hemorrhage, or calcification. The typical density on nonenhanced CT is greater than 10 HU. On enhanced CT, the mass is usually vascular, and T2-weighted MRI will show a lesion more intense than liver tissue.⁶

Adrenocortical carcinoma is also not classically associated with autologous activity, and so is not likely to explain our patient’s symptoms.⁶

Metastatic disease can present with masses of variable size, often bilaterally, and occasionally with cysts or areas of hemorrhage. The typical density of metastatic lesions on nonenhanced CT is greater than 10 HU. On enhanced CT, they are usually vascular, and on T2-weighted MRI they are hyperintense.⁶ The characteristics of the mass and the absence of a primary malignancy on CT of the chest and abdomen do not support the diagnosis of metastatic disease.

Pheochromocytoma is a neuroendocrine tumor of the adrenal medulla that can present as a large heterogeneous mass, greater than 3 cm in diameter, with clear margins and cysts or areas of hemorrhage. Extra-adrenal neuroendocrine tumors are typically called paragangliomas and have features similar to those of pheochromocytoma. The typical density of pheochromocytoma on nonenhanced CT is greater than 10 HU. On enhanced CT, it is usually vascular, and T2-weighted MRI shows a hyperintense lesion. Pheochromocytoma can be biochemically active and thus can cause signs and symptoms that will lead to the diagnosis.⁶

Other imaging tests may play a role in the evaluation of adrenal masses but are not required for the diagnosis of pheochromocytoma. Functional positron emission tomography using metaiodobenzylguanidine labeled with iodine 123 or-iodine 131 or using the glucose analogue F-18 fluorodeoxyglucose has been used in the initial assessment of pheochromocytoma, with good sensitivity and specificity.^7,8

Our patient’s pacemaker-defibrillator precluded him from undergoing MRI.

DIAGNOSIS: PHEOCHROMOCYTOMA

Pheochromocytoma was highly suspected on the basis of the patient’s clinical presentation, and metoprolol was immediately discontinued. He was started on the calcium channel blocker verapamil and the alpha-blocker phenoxybenzamine.

Serum samples were obtained to measure metanephrines, dehydroepiandrosterone, aldosterone, and cortisol, and a 24-hour urine collection was obtained to measure creatinine, dopamine, epinephrine, norepinephrine, cortisol, and metanephrines. Based on the results (Table 1) and on the findings on imaging, the patient was diagnosed with pheochromocytoma. A surgical consultation was obtained, and surgery was recommended.

WHEN DOES PHEOCHROMOCYTOMA CALL FOR SURGERY?

3. Which criterion is most important when determining the need for surgery for pheochromocytoma?

• Findings on fine-needle aspiration biopsy
• Biochemical activity
• Size of the mass
• Bilateral masses

Fine-needle aspiration biopsy can be done when a mass is found incidentally and no evidence of biochemical activity is detected, although it is not an essential part of the diagnostic workup.⁹ In most cases, the sampling from fine-needle aspiration is not sufficient to achieve a diagnosis.

Biochemical activity is the most important factor when determining the need for prompt surgical intervention. The excess circulating catecholamines have been associated with increased risk of cardiovascular morbidity and death independent of the morbidity associated with hypertension alone.¹⁰ Biochemical activity can be independent of the size of the mass, but larger masses typically present with symptoms.

Bilateral masses have been associated with metastatic disease.¹¹ In retrospect, the patient’s history of hypertension and cerebrovascular accident could be associated with the development of a catecholamine-releasing tumor.

A GOOD OUTCOME FROM SURGERY

The patient was continued on phenoxybenzamine for 7 days and responded well to this therapy.

After this preoperative preparation, he underwent laparoscopic right adrenalectomy with excision of a retroperitoneal adrenal mass. His postoperative course was complicated by transient hypotension requiring low-dose vasopressin support for less than 24 hours. He was then restarted on his previous dosage of metoprolol and was discharged home on postoperative day 5 with stable blood pressure. Follow-up 24-hour urine collection 1 month after he was discharged showed normalization of metanephrine, normetanephrine, epinephrine, and norepinephrine levels.

Despite low suspicion for an underlying genetic syndrome, he was referred for genetic testing and was scheduled to have a repeat 24-hour urine collection and imaging in 6 months to follow his enlarged left adrenal gland, which did not appear to be metabolically hyperactive.

4. What is the most common perioperative complication of pheochromocytoma excision?

• Hypoglycemia
• Hypotension
• Hypocortisolism
• Hypertension
• Tachycardia

Hypoglycemia has been observed after removal of pheochromocytoma, as levels of catecholamines (which normally inhibit pancreatic beta cells) decrease and insulin secretion consequently increases.¹² Our patient developed hypoglycemia before surgery, not after, and it was likely due to the combination of his antidiabetic therapy, weight loss, and decreased oral intake.

Hypotension is the most common complication in the perioperative period. It is associated with excessive loss of catecholamine secretion. It is usually short-lived but may require aggressive administration of intravenous fluids and use of sympathomimetic agents.

Hypocortisolism is unlikely in patients with pheochromocytoma, but it is likely after removal of adrenocortical adenoma.

Hypertension and tachycardia affect up to 40% of pheochromocytoma patients in some case series.¹²

PHEOCHROMOCYTOMA: A CATECHOLAMINE-SECRETING TUMOR

The pathophysiology of pheochromocytoma is complex. It is characterized by accelerated growth of cells producing catecholamines, which may produce symptoms when secreted into the bloodstream. The classic triad of symptoms is headache, hypertension, and hyperglycemia, although our patient had very low blood sugar levels. Other common symptoms are nausea, orthostasis, and tremor, although not all symptoms are invariably seen.

Genetic testing recommended

Genetic associations have been described and are thought to be responsible for 20% to 30% of cases of pheochromocytoma. All associated germline mutations are autosomal dominant, some with variable penetrance. These include:

• Succinate dehydrogenase subunit B, C, and D mutations
• von Hippel-Lindau syndrome
• Multiple endocrine neoplasia type 1 and type 2 syndromes
• Neurofibromatosis type 1.^13,14

The succinate dehydrogenase subunit mutations have been associated with, but not limited to, extra-adrenal adenomas (paragangliomas) and carry a worse prognosis.

Some experts recommend genetic testing in all cases of pheochromocytoma, sporadic or familial, and this testing should be followed by counseling if a mutation is found.¹⁵ Others recommend genetic testing based on the patient’s age (under age 50), history, imaging, and biochemical features of the tumor (metanephrines predominate in multiple endocrine neoplasia syndromes, and normetanephrines in von Hippel-Lindau syndrome).¹³

Serious consequences

A thorough evaluation is recommended, since pheochromocytoma has been associated with increased cardiovascular morbidity. In a retrospective series, Stolk et al¹⁰ reported that patients with pheochromocytoma had a higher incidence of myocardial infarction, angina, and stroke in the years preceding the diagnosis than did patients with essential hypertension (13.8% vs 1.1%, P < .001).¹⁰

Catecholamine cardiomyopathy has been described and shares clinical features with Takotsubo or stress cardiomyopathy, with global left ventricular systolic and diastolic dysfunction that improve or resolve after the adrenergic insult is removed.¹⁶

Conditions that warrant further evaluation or that may suggest pheochromocytoma are malignant hypertension, hypertensive encephalopathy, ischemic stroke, subarachnoid hemorrhage, acute pulmonary edema, angina pectoris, myocardial infarction, aortic dissection, and kidney injury.

When to suspect pheochromocytoma

Pheochromocytoma should be suspected in a patient with resistant hypertension, family history, or imaging findings that suggest an adrenal mass with a heterogeneous appearance. The diagnostic algorithm follows the same pathway as for the evaluation of an incidentally found adrenal mass, with determination of its dimension and characteristics by CT or MRI, and with biochemical testing of urine catecholamines, plasma free metanephrines, renin, aldosterone, and cortisol.

The diagnosis of pheochromocytoma is established by obtaining fractionated metanephrines and catecholamines in a 24-hour urine collection (sensitivity 90%, specificity 98%). Analysis of plasma metanephrines has a higher sensitivity (97%) but lower specificity (85%).¹⁷ The combination of typical signs, symptoms, and laboratory findings makes the diagnosis likely, especially in combination with a unilateral adrenal mass.

Laparoscopic surgery after medical preparation for active tumors

If the mass appears benign and not biochemically hyperactive, then follow-up at 1 year is recommended, with repeat testing. Surgical evaluation and intervention is recommended for lesions that appear malignant or that are biochemically active and clinically symptomatic.⁹

Preoperative hemodynamic control is essential in the management of pheochromocytoma to prevent or minimize hemodynamic changes that can be driven by increased catecholamines. Control is typically achieved with initial alpha-blockade and then beta-blockade to avoid worsening hypertension and to prevent an acute hypertensive crisis during surgical intervention. Phenoxybenzamine, the mainstay of therapy, is a nonselective alpha-blocker with a long duration of action that requires titration over several days up to 3 weeks.

A selective alpha-1-blocker such as doxazosin can be used to control postoperative hypotension, as it has a shorter half-life than phenoxybenzamine. Alternative strategies include calcium channel blockers, centrally acting sympathetic blockers, and magnesium.¹⁸

Laparoscopic adrenalectomy by an experienced surgeon after excellent medical preparation is often considered the treatment of choice, but for larger or malignant masses, an open procedure is recommended. The risk of perioperative morbidity and death can be reduced by adequate medical management. With successful surgical resection, the long-term prognosis is favorable.

A 61-year-old man with type 2 diabetes mellitus on glimepiride therapy presented with somnolence and slurred speech. His capillary glucose level was 17 mg/dL and his serum glucose level was 28 mg/dL. He was treated with intravenous dextrose, and his glucose level promptly returned to normal.

He had been adherent to his medication regimen and denied overmedicating or accidental overdosing. Over the past 7 months, he had noted redness on his palms, a rash on his legs, intermittent moderate to severe headaches, weight loss, and decreased appetite. In addition, his blood pressure had been labile, which his physicians had attributed to autonomic instability. He had continued on the same dose of glimepiride despite losing weight.

His history included multivessel coronary artery disease treated with angioplasty and placement of multiple coronary stents; ischemic cardiomyopathy with a left ventricular ejection fraction of 28%; implantation of a cardioverter-defibrillator for secondary prevention of ventricular arrhythmia; an ischemic stroke; and multiple sclerosis complicated by bilateral blindness, with optic nerve involvement and autonomic instability, present for over a year and manifested by labile blood pressure. He was a long-time tobacco user. His daily medications included ticagrelor 90 mg, aspirin 81 mg, metoprolol 50 mg, ramipril 10 mg, simvastatin 20 mg, glimepiride 2 mg, and esomeprazole 40 mg. He needed help taking his medications.

At the time of hospital admission, his heart rate was 69 beats per minute with a regular rhythm, blood pressure 115/73 mm Hg, respiratory rate 11 breaths per minute with an oxygen saturation of 99% on room air, and oral temperature 34.7°C (94.5°F). He appeared to be in no distress.

Cardiovascular examination revealed no murmurs or gallops; there was mild nonpitting edema of the lower extremities. Pulmonary, abdominal, and neurologic examinations were unrevealing except for bilateral blindness. Vascular examination revealed no bruits. Results of a complete blood cell count and metabolic panel were normal except for a hemoglobin level of 9.9 g/dL (reference range 13.5–17.5) and a platelet count of 477 × 10⁹/L (150–450).

Although he continued to receive the same medications he had been taking at home, his blood pressure fluctuated. On the second hospital day, it reached 186/135 mm Hg, at which time he also had palpitations, dyspnea, and crackles in the lower lobes of both lungs. Volume resuscitation on admission was suspected to have played a role, and he received furosemide, which improved his symptoms. But several hours later, his blood pressure rose again, and he became diaphoretic. Despite aggressive treatment with different antihypertensive agents, his blood pressure remained high and his symptoms persisted. Chest radiography showed no evidence of pulmonary edema. Because of his progressive dyspnea, the diagnosis of pulmonary embolism was entertained.

CAUSES OF RESISTANT HYPERTENSION

1. What could explain this patient’s high blood pressure?

• A drug effect
• Renovascular disease
• Excess circulating catecholamines
• Obstructive sleep apnea
• Primary aldosteronism

Sympathomimetic drugs such as epinephrine, norepinephrine, dopamine, and vasopressin, which are used when hemodynamic support is required, can raise both systolic and diastolic blood pressure. Nonsteroidal anti-inflammatory drugs and nasal decongestants are common culprits in the community. However, our patient was using none of these drugs.

Renovascular disease is one of many causes of resistant hypertension, accounting for 8% of all cases.^1,2 Despite fluctuations, the blood pressure often remains chronically elevated, its changes are less paroxysmal than in our patient, and a precipitating factor such as a dietary indiscretion is sometimes identified.¹

Excess circulating catecholamines can be a result of stress, exogenous administration, or endogenous oversecretion. Our patient’s clinical presentation is highly suspicious for a high-catecholamine state, and this should be further evaluated.

Obstructive sleep apnea is common in patients with resistant hypertension, with an estimated prevalence as high as 60% in this group.^3,4

Primary aldosteronism has an estimated prevalence of about 20% in patients evaluated for resistant hypertension.⁵

AN ADRENAL MASS IS INCIDENTALLY DISCOVERED

Computed tomographic angiography of the chest revealed no evidence of pulmonary emboli. There was mild dilation of the central pulmonary arteries and an incidental, incompletely imaged 4.7-by-3.4-cm mass of mixed attenuation in the right adrenal gland, with macroscopic fat within the lesion.

Computed tomography (CT) of the abdomen with dedicated cuts through the adrenal glands revealed a 4.7-cm heterogeneous right adrenal mass with a density of 34 Hounsfield units (HU). The left adrenal gland appeared diffusely enlarged without a discretely seen mass, consistent with hyperplasticity (Figure 1).

2. Based on the patient’s clinical presentation and findings on CT, what would be the most likely diagnosis for this incidentally found adrenal mass?

• Adrenocortical adenoma
• Adrenocortical carcinoma
• Metastatic mass
• Pheochromocytoma

Adrenocortical adenoma can present as a small homogeneous mass of variable size, with smooth margins, and rarely containing hemorrhagic tissue or calcifications. The typical density on nonenhanced CT is less than 10 HU. On enhanced CT, it is nonvascular. T2-weighted magnetic resonance imaging (MRI) shows a lesion of the same intensity as liver tissue.⁶

Adrenocortical adenoma is not classically associated with autologous activity and thus is less likely to explain our patient’s symptoms.

Adrenocortical carcinoma can present as a large heterogeneous mass, usually greater than 4 cm in diameter, with irregular margins and areas of necrosis, hemorrhage, or calcification. The typical density on nonenhanced CT is greater than 10 HU. On enhanced CT, the mass is usually vascular, and T2-weighted MRI will show a lesion more intense than liver tissue.⁶

Adrenocortical carcinoma is also not classically associated with autologous activity, and so is not likely to explain our patient’s symptoms.⁶

Metastatic disease can present with masses of variable size, often bilaterally, and occasionally with cysts or areas of hemorrhage. The typical density of metastatic lesions on nonenhanced CT is greater than 10 HU. On enhanced CT, they are usually vascular, and on T2-weighted MRI they are hyperintense.⁶ The characteristics of the mass and the absence of a primary malignancy on CT of the chest and abdomen do not support the diagnosis of metastatic disease.

Pheochromocytoma is a neuroendocrine tumor of the adrenal medulla that can present as a large heterogeneous mass, greater than 3 cm in diameter, with clear margins and cysts or areas of hemorrhage. Extra-adrenal neuroendocrine tumors are typically called paragangliomas and have features similar to those of pheochromocytoma. The typical density of pheochromocytoma on nonenhanced CT is greater than 10 HU. On enhanced CT, it is usually vascular, and T2-weighted MRI shows a hyperintense lesion. Pheochromocytoma can be biochemically active and thus can cause signs and symptoms that will lead to the diagnosis.⁶

Other imaging tests may play a role in the evaluation of adrenal masses but are not required for the diagnosis of pheochromocytoma. Functional positron emission tomography using metaiodobenzylguanidine labeled with iodine 123 or-iodine 131 or using the glucose analogue F-18 fluorodeoxyglucose has been used in the initial assessment of pheochromocytoma, with good sensitivity and specificity.^7,8

Our patient’s pacemaker-defibrillator precluded him from undergoing MRI.

DIAGNOSIS: PHEOCHROMOCYTOMA

Pheochromocytoma was highly suspected on the basis of the patient’s clinical presentation, and metoprolol was immediately discontinued. He was started on the calcium channel blocker verapamil and the alpha-blocker phenoxybenzamine.

Serum samples were obtained to measure metanephrines, dehydroepiandrosterone, aldosterone, and cortisol, and a 24-hour urine collection was obtained to measure creatinine, dopamine, epinephrine, norepinephrine, cortisol, and metanephrines. Based on the results (Table 1) and on the findings on imaging, the patient was diagnosed with pheochromocytoma. A surgical consultation was obtained, and surgery was recommended.

WHEN DOES PHEOCHROMOCYTOMA CALL FOR SURGERY?

3. Which criterion is most important when determining the need for surgery for pheochromocytoma?

• Findings on fine-needle aspiration biopsy
• Biochemical activity
• Size of the mass
• Bilateral masses

Fine-needle aspiration biopsy can be done when a mass is found incidentally and no evidence of biochemical activity is detected, although it is not an essential part of the diagnostic workup.⁹ In most cases, the sampling from fine-needle aspiration is not sufficient to achieve a diagnosis.

Biochemical activity is the most important factor when determining the need for prompt surgical intervention. The excess circulating catecholamines have been associated with increased risk of cardiovascular morbidity and death independent of the morbidity associated with hypertension alone.¹⁰ Biochemical activity can be independent of the size of the mass, but larger masses typically present with symptoms.

Bilateral masses have been associated with metastatic disease.¹¹ In retrospect, the patient’s history of hypertension and cerebrovascular accident could be associated with the development of a catecholamine-releasing tumor.

A GOOD OUTCOME FROM SURGERY

The patient was continued on phenoxybenzamine for 7 days and responded well to this therapy.

After this preoperative preparation, he underwent laparoscopic right adrenalectomy with excision of a retroperitoneal adrenal mass. His postoperative course was complicated by transient hypotension requiring low-dose vasopressin support for less than 24 hours. He was then restarted on his previous dosage of metoprolol and was discharged home on postoperative day 5 with stable blood pressure. Follow-up 24-hour urine collection 1 month after he was discharged showed normalization of metanephrine, normetanephrine, epinephrine, and norepinephrine levels.

Despite low suspicion for an underlying genetic syndrome, he was referred for genetic testing and was scheduled to have a repeat 24-hour urine collection and imaging in 6 months to follow his enlarged left adrenal gland, which did not appear to be metabolically hyperactive.

4. What is the most common perioperative complication of pheochromocytoma excision?

• Hypoglycemia
• Hypotension
• Hypocortisolism
• Hypertension
• Tachycardia

Hypoglycemia has been observed after removal of pheochromocytoma, as levels of catecholamines (which normally inhibit pancreatic beta cells) decrease and insulin secretion consequently increases.¹² Our patient developed hypoglycemia before surgery, not after, and it was likely due to the combination of his antidiabetic therapy, weight loss, and decreased oral intake.

Hypotension is the most common complication in the perioperative period. It is associated with excessive loss of catecholamine secretion. It is usually short-lived but may require aggressive administration of intravenous fluids and use of sympathomimetic agents.

Hypocortisolism is unlikely in patients with pheochromocytoma, but it is likely after removal of adrenocortical adenoma.

Hypertension and tachycardia affect up to 40% of pheochromocytoma patients in some case series.¹²

PHEOCHROMOCYTOMA: A CATECHOLAMINE-SECRETING TUMOR

The pathophysiology of pheochromocytoma is complex. It is characterized by accelerated growth of cells producing catecholamines, which may produce symptoms when secreted into the bloodstream. The classic triad of symptoms is headache, hypertension, and hyperglycemia, although our patient had very low blood sugar levels. Other common symptoms are nausea, orthostasis, and tremor, although not all symptoms are invariably seen.

Genetic testing recommended

Genetic associations have been described and are thought to be responsible for 20% to 30% of cases of pheochromocytoma. All associated germline mutations are autosomal dominant, some with variable penetrance. These include:

• Succinate dehydrogenase subunit B, C, and D mutations
• von Hippel-Lindau syndrome
• Multiple endocrine neoplasia type 1 and type 2 syndromes
• Neurofibromatosis type 1.^13,14

The succinate dehydrogenase subunit mutations have been associated with, but not limited to, extra-adrenal adenomas (paragangliomas) and carry a worse prognosis.

Some experts recommend genetic testing in all cases of pheochromocytoma, sporadic or familial, and this testing should be followed by counseling if a mutation is found.¹⁵ Others recommend genetic testing based on the patient’s age (under age 50), history, imaging, and biochemical features of the tumor (metanephrines predominate in multiple endocrine neoplasia syndromes, and normetanephrines in von Hippel-Lindau syndrome).¹³

Serious consequences

A thorough evaluation is recommended, since pheochromocytoma has been associated with increased cardiovascular morbidity. In a retrospective series, Stolk et al¹⁰ reported that patients with pheochromocytoma had a higher incidence of myocardial infarction, angina, and stroke in the years preceding the diagnosis than did patients with essential hypertension (13.8% vs 1.1%, P < .001).¹⁰

Catecholamine cardiomyopathy has been described and shares clinical features with Takotsubo or stress cardiomyopathy, with global left ventricular systolic and diastolic dysfunction that improve or resolve after the adrenergic insult is removed.¹⁶

Conditions that warrant further evaluation or that may suggest pheochromocytoma are malignant hypertension, hypertensive encephalopathy, ischemic stroke, subarachnoid hemorrhage, acute pulmonary edema, angina pectoris, myocardial infarction, aortic dissection, and kidney injury.

When to suspect pheochromocytoma

Pheochromocytoma should be suspected in a patient with resistant hypertension, family history, or imaging findings that suggest an adrenal mass with a heterogeneous appearance. The diagnostic algorithm follows the same pathway as for the evaluation of an incidentally found adrenal mass, with determination of its dimension and characteristics by CT or MRI, and with biochemical testing of urine catecholamines, plasma free metanephrines, renin, aldosterone, and cortisol.

The diagnosis of pheochromocytoma is established by obtaining fractionated metanephrines and catecholamines in a 24-hour urine collection (sensitivity 90%, specificity 98%). Analysis of plasma metanephrines has a higher sensitivity (97%) but lower specificity (85%).¹⁷ The combination of typical signs, symptoms, and laboratory findings makes the diagnosis likely, especially in combination with a unilateral adrenal mass.

Laparoscopic surgery after medical preparation for active tumors

If the mass appears benign and not biochemically hyperactive, then follow-up at 1 year is recommended, with repeat testing. Surgical evaluation and intervention is recommended for lesions that appear malignant or that are biochemically active and clinically symptomatic.⁹

Preoperative hemodynamic control is essential in the management of pheochromocytoma to prevent or minimize hemodynamic changes that can be driven by increased catecholamines. Control is typically achieved with initial alpha-blockade and then beta-blockade to avoid worsening hypertension and to prevent an acute hypertensive crisis during surgical intervention. Phenoxybenzamine, the mainstay of therapy, is a nonselective alpha-blocker with a long duration of action that requires titration over several days up to 3 weeks.

A selective alpha-1-blocker such as doxazosin can be used to control postoperative hypotension, as it has a shorter half-life than phenoxybenzamine. Alternative strategies include calcium channel blockers, centrally acting sympathetic blockers, and magnesium.¹⁸

Laparoscopic adrenalectomy by an experienced surgeon after excellent medical preparation is often considered the treatment of choice, but for larger or malignant masses, an open procedure is recommended. The risk of perioperative morbidity and death can be reduced by adequate medical management. With successful surgical resection, the long-term prognosis is favorable.

A 61-year-old man with type 2 diabetes mellitus on glimepiride therapy presented with somnolence and slurred speech. His capillary glucose level was 17 mg/dL and his serum glucose level was 28 mg/dL. He was treated with intravenous dextrose, and his glucose level promptly returned to normal.

He had been adherent to his medication regimen and denied overmedicating or accidental overdosing. Over the past 7 months, he had noted redness on his palms, a rash on his legs, intermittent moderate to severe headaches, weight loss, and decreased appetite. In addition, his blood pressure had been labile, which his physicians had attributed to autonomic instability. He had continued on the same dose of glimepiride despite losing weight.

His history included multivessel coronary artery disease treated with angioplasty and placement of multiple coronary stents; ischemic cardiomyopathy with a left ventricular ejection fraction of 28%; implantation of a cardioverter-defibrillator for secondary prevention of ventricular arrhythmia; an ischemic stroke; and multiple sclerosis complicated by bilateral blindness, with optic nerve involvement and autonomic instability, present for over a year and manifested by labile blood pressure. He was a long-time tobacco user. His daily medications included ticagrelor 90 mg, aspirin 81 mg, metoprolol 50 mg, ramipril 10 mg, simvastatin 20 mg, glimepiride 2 mg, and esomeprazole 40 mg. He needed help taking his medications.

At the time of hospital admission, his heart rate was 69 beats per minute with a regular rhythm, blood pressure 115/73 mm Hg, respiratory rate 11 breaths per minute with an oxygen saturation of 99% on room air, and oral temperature 34.7°C (94.5°F). He appeared to be in no distress.

Cardiovascular examination revealed no murmurs or gallops; there was mild nonpitting edema of the lower extremities. Pulmonary, abdominal, and neurologic examinations were unrevealing except for bilateral blindness. Vascular examination revealed no bruits. Results of a complete blood cell count and metabolic panel were normal except for a hemoglobin level of 9.9 g/dL (reference range 13.5–17.5) and a platelet count of 477 × 10⁹/L (150–450).

Although he continued to receive the same medications he had been taking at home, his blood pressure fluctuated. On the second hospital day, it reached 186/135 mm Hg, at which time he also had palpitations, dyspnea, and crackles in the lower lobes of both lungs. Volume resuscitation on admission was suspected to have played a role, and he received furosemide, which improved his symptoms. But several hours later, his blood pressure rose again, and he became diaphoretic. Despite aggressive treatment with different antihypertensive agents, his blood pressure remained high and his symptoms persisted. Chest radiography showed no evidence of pulmonary edema. Because of his progressive dyspnea, the diagnosis of pulmonary embolism was entertained.

CAUSES OF RESISTANT HYPERTENSION

1. What could explain this patient’s high blood pressure?

• A drug effect
• Renovascular disease
• Excess circulating catecholamines
• Obstructive sleep apnea
• Primary aldosteronism

Sympathomimetic drugs such as epinephrine, norepinephrine, dopamine, and vasopressin, which are used when hemodynamic support is required, can raise both systolic and diastolic blood pressure. Nonsteroidal anti-inflammatory drugs and nasal decongestants are common culprits in the community. However, our patient was using none of these drugs.

Renovascular disease is one of many causes of resistant hypertension, accounting for 8% of all cases.^1,2 Despite fluctuations, the blood pressure often remains chronically elevated, its changes are less paroxysmal than in our patient, and a precipitating factor such as a dietary indiscretion is sometimes identified.¹

Excess circulating catecholamines can be a result of stress, exogenous administration, or endogenous oversecretion. Our patient’s clinical presentation is highly suspicious for a high-catecholamine state, and this should be further evaluated.

Obstructive sleep apnea is common in patients with resistant hypertension, with an estimated prevalence as high as 60% in this group.^3,4

Primary aldosteronism has an estimated prevalence of about 20% in patients evaluated for resistant hypertension.⁵

AN ADRENAL MASS IS INCIDENTALLY DISCOVERED

Computed tomographic angiography of the chest revealed no evidence of pulmonary emboli. There was mild dilation of the central pulmonary arteries and an incidental, incompletely imaged 4.7-by-3.4-cm mass of mixed attenuation in the right adrenal gland, with macroscopic fat within the lesion.

Computed tomography (CT) of the abdomen with dedicated cuts through the adrenal glands revealed a 4.7-cm heterogeneous right adrenal mass with a density of 34 Hounsfield units (HU). The left adrenal gland appeared diffusely enlarged without a discretely seen mass, consistent with hyperplasticity (Figure 1).

2. Based on the patient’s clinical presentation and findings on CT, what would be the most likely diagnosis for this incidentally found adrenal mass?

• Adrenocortical adenoma
• Adrenocortical carcinoma
• Metastatic mass
• Pheochromocytoma

Adrenocortical adenoma can present as a small homogeneous mass of variable size, with smooth margins, and rarely containing hemorrhagic tissue or calcifications. The typical density on nonenhanced CT is less than 10 HU. On enhanced CT, it is nonvascular. T2-weighted magnetic resonance imaging (MRI) shows a lesion of the same intensity as liver tissue.⁶

Adrenocortical adenoma is not classically associated with autologous activity and thus is less likely to explain our patient’s symptoms.

Adrenocortical carcinoma can present as a large heterogeneous mass, usually greater than 4 cm in diameter, with irregular margins and areas of necrosis, hemorrhage, or calcification. The typical density on nonenhanced CT is greater than 10 HU. On enhanced CT, the mass is usually vascular, and T2-weighted MRI will show a lesion more intense than liver tissue.⁶

Adrenocortical carcinoma is also not classically associated with autologous activity, and so is not likely to explain our patient’s symptoms.⁶

Metastatic disease can present with masses of variable size, often bilaterally, and occasionally with cysts or areas of hemorrhage. The typical density of metastatic lesions on nonenhanced CT is greater than 10 HU. On enhanced CT, they are usually vascular, and on T2-weighted MRI they are hyperintense.⁶ The characteristics of the mass and the absence of a primary malignancy on CT of the chest and abdomen do not support the diagnosis of metastatic disease.

Pheochromocytoma is a neuroendocrine tumor of the adrenal medulla that can present as a large heterogeneous mass, greater than 3 cm in diameter, with clear margins and cysts or areas of hemorrhage. Extra-adrenal neuroendocrine tumors are typically called paragangliomas and have features similar to those of pheochromocytoma. The typical density of pheochromocytoma on nonenhanced CT is greater than 10 HU. On enhanced CT, it is usually vascular, and T2-weighted MRI shows a hyperintense lesion. Pheochromocytoma can be biochemically active and thus can cause signs and symptoms that will lead to the diagnosis.⁶

Other imaging tests may play a role in the evaluation of adrenal masses but are not required for the diagnosis of pheochromocytoma. Functional positron emission tomography using metaiodobenzylguanidine labeled with iodine 123 or-iodine 131 or using the glucose analogue F-18 fluorodeoxyglucose has been used in the initial assessment of pheochromocytoma, with good sensitivity and specificity.^7,8

Our patient’s pacemaker-defibrillator precluded him from undergoing MRI.

DIAGNOSIS: PHEOCHROMOCYTOMA

Pheochromocytoma was highly suspected on the basis of the patient’s clinical presentation, and metoprolol was immediately discontinued. He was started on the calcium channel blocker verapamil and the alpha-blocker phenoxybenzamine.

Serum samples were obtained to measure metanephrines, dehydroepiandrosterone, aldosterone, and cortisol, and a 24-hour urine collection was obtained to measure creatinine, dopamine, epinephrine, norepinephrine, cortisol, and metanephrines. Based on the results (Table 1) and on the findings on imaging, the patient was diagnosed with pheochromocytoma. A surgical consultation was obtained, and surgery was recommended.

WHEN DOES PHEOCHROMOCYTOMA CALL FOR SURGERY?

3. Which criterion is most important when determining the need for surgery for pheochromocytoma?

• Findings on fine-needle aspiration biopsy
• Biochemical activity
• Size of the mass
• Bilateral masses

Fine-needle aspiration biopsy can be done when a mass is found incidentally and no evidence of biochemical activity is detected, although it is not an essential part of the diagnostic workup.⁹ In most cases, the sampling from fine-needle aspiration is not sufficient to achieve a diagnosis.

Biochemical activity is the most important factor when determining the need for prompt surgical intervention. The excess circulating catecholamines have been associated with increased risk of cardiovascular morbidity and death independent of the morbidity associated with hypertension alone.¹⁰ Biochemical activity can be independent of the size of the mass, but larger masses typically present with symptoms.

Bilateral masses have been associated with metastatic disease.¹¹ In retrospect, the patient’s history of hypertension and cerebrovascular accident could be associated with the development of a catecholamine-releasing tumor.

A GOOD OUTCOME FROM SURGERY

The patient was continued on phenoxybenzamine for 7 days and responded well to this therapy.

After this preoperative preparation, he underwent laparoscopic right adrenalectomy with excision of a retroperitoneal adrenal mass. His postoperative course was complicated by transient hypotension requiring low-dose vasopressin support for less than 24 hours. He was then restarted on his previous dosage of metoprolol and was discharged home on postoperative day 5 with stable blood pressure. Follow-up 24-hour urine collection 1 month after he was discharged showed normalization of metanephrine, normetanephrine, epinephrine, and norepinephrine levels.

Despite low suspicion for an underlying genetic syndrome, he was referred for genetic testing and was scheduled to have a repeat 24-hour urine collection and imaging in 6 months to follow his enlarged left adrenal gland, which did not appear to be metabolically hyperactive.

4. What is the most common perioperative complication of pheochromocytoma excision?

• Hypoglycemia
• Hypotension
• Hypocortisolism
• Hypertension
• Tachycardia

Hypoglycemia has been observed after removal of pheochromocytoma, as levels of catecholamines (which normally inhibit pancreatic beta cells) decrease and insulin secretion consequently increases.¹² Our patient developed hypoglycemia before surgery, not after, and it was likely due to the combination of his antidiabetic therapy, weight loss, and decreased oral intake.

Hypotension is the most common complication in the perioperative period. It is associated with excessive loss of catecholamine secretion. It is usually short-lived but may require aggressive administration of intravenous fluids and use of sympathomimetic agents.

Hypocortisolism is unlikely in patients with pheochromocytoma, but it is likely after removal of adrenocortical adenoma.

Hypertension and tachycardia affect up to 40% of pheochromocytoma patients in some case series.¹²

PHEOCHROMOCYTOMA: A CATECHOLAMINE-SECRETING TUMOR

The pathophysiology of pheochromocytoma is complex. It is characterized by accelerated growth of cells producing catecholamines, which may produce symptoms when secreted into the bloodstream. The classic triad of symptoms is headache, hypertension, and hyperglycemia, although our patient had very low blood sugar levels. Other common symptoms are nausea, orthostasis, and tremor, although not all symptoms are invariably seen.

Genetic testing recommended

Genetic associations have been described and are thought to be responsible for 20% to 30% of cases of pheochromocytoma. All associated germline mutations are autosomal dominant, some with variable penetrance. These include:

• Succinate dehydrogenase subunit B, C, and D mutations
• von Hippel-Lindau syndrome
• Multiple endocrine neoplasia type 1 and type 2 syndromes
• Neurofibromatosis type 1.^13,14

The succinate dehydrogenase subunit mutations have been associated with, but not limited to, extra-adrenal adenomas (paragangliomas) and carry a worse prognosis.

Some experts recommend genetic testing in all cases of pheochromocytoma, sporadic or familial, and this testing should be followed by counseling if a mutation is found.¹⁵ Others recommend genetic testing based on the patient’s age (under age 50), history, imaging, and biochemical features of the tumor (metanephrines predominate in multiple endocrine neoplasia syndromes, and normetanephrines in von Hippel-Lindau syndrome).¹³

Serious consequences

A thorough evaluation is recommended, since pheochromocytoma has been associated with increased cardiovascular morbidity. In a retrospective series, Stolk et al¹⁰ reported that patients with pheochromocytoma had a higher incidence of myocardial infarction, angina, and stroke in the years preceding the diagnosis than did patients with essential hypertension (13.8% vs 1.1%, P < .001).¹⁰

Catecholamine cardiomyopathy has been described and shares clinical features with Takotsubo or stress cardiomyopathy, with global left ventricular systolic and diastolic dysfunction that improve or resolve after the adrenergic insult is removed.¹⁶

Conditions that warrant further evaluation or that may suggest pheochromocytoma are malignant hypertension, hypertensive encephalopathy, ischemic stroke, subarachnoid hemorrhage, acute pulmonary edema, angina pectoris, myocardial infarction, aortic dissection, and kidney injury.

When to suspect pheochromocytoma

Pheochromocytoma should be suspected in a patient with resistant hypertension, family history, or imaging findings that suggest an adrenal mass with a heterogeneous appearance. The diagnostic algorithm follows the same pathway as for the evaluation of an incidentally found adrenal mass, with determination of its dimension and characteristics by CT or MRI, and with biochemical testing of urine catecholamines, plasma free metanephrines, renin, aldosterone, and cortisol.

The diagnosis of pheochromocytoma is established by obtaining fractionated metanephrines and catecholamines in a 24-hour urine collection (sensitivity 90%, specificity 98%). Analysis of plasma metanephrines has a higher sensitivity (97%) but lower specificity (85%).¹⁷ The combination of typical signs, symptoms, and laboratory findings makes the diagnosis likely, especially in combination with a unilateral adrenal mass.

Laparoscopic surgery after medical preparation for active tumors

If the mass appears benign and not biochemically hyperactive, then follow-up at 1 year is recommended, with repeat testing. Surgical evaluation and intervention is recommended for lesions that appear malignant or that are biochemically active and clinically symptomatic.⁹

Preoperative hemodynamic control is essential in the management of pheochromocytoma to prevent or minimize hemodynamic changes that can be driven by increased catecholamines. Control is typically achieved with initial alpha-blockade and then beta-blockade to avoid worsening hypertension and to prevent an acute hypertensive crisis during surgical intervention. Phenoxybenzamine, the mainstay of therapy, is a nonselective alpha-blocker with a long duration of action that requires titration over several days up to 3 weeks.

A selective alpha-1-blocker such as doxazosin can be used to control postoperative hypotension, as it has a shorter half-life than phenoxybenzamine. Alternative strategies include calcium channel blockers, centrally acting sympathetic blockers, and magnesium.¹⁸

Laparoscopic adrenalectomy by an experienced surgeon after excellent medical preparation is often considered the treatment of choice, but for larger or malignant masses, an open procedure is recommended. The risk of perioperative morbidity and death can be reduced by adequate medical management. With successful surgical resection, the long-term prognosis is favorable.

A 50-year-old man with hypertension presents to the internal medicine clinic. He has been an active smoker for 15 years and smokes 1 pack of cigarettes a day. He was recently diagnosed with type 2 diabetes mellitus after routine blood work revealed his hemoglobin A_1c level was elevated at 7.5%. He has no current complaints but is concerned about his future risk of a heart attack or stroke.

See related commentary

THE BURDEN OF DIABETES MELLITUS

The prevalence of diabetes mellitus in US adults (age > 20) has tripled during the last 30 years to 28.9 million, or 12% of the population in this age group.¹ Globally, 382 million people had a diagnosis of diabetes in 2013, and with the increasing prevalence of obesity and adoption of a Western diet, this number is expected to escalate to 592 million by 2035.²

HOW GREAT IS THE CARDIOVASCULAR RISK IN PEOPLE WITH DIABETES?

Seshasai SR, et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 2011; 364:829–841.Copyright 2011 Massachusetts Medical Society (MMS). Reprinted with permission from MMS.

Diabetes mellitus is linked to a twofold increase in the risk of adverse cardiovascular events even after adjusting for risk from hypertension and smoking.³ In early studies, diabetic people with no history of myocardial infarction were shown to have a lifetime risk of infarction similar to that in nondiabetic people who had already had an infarction,⁴ thus establishing diabetes as a “coronary artery disease equivalent.” Middle-aged men diagnosed with diabetes lose an average of 6 years of life and women lose 7 years compared with those without diabetes, with cardiovascular morbidity contributing to more than half of this reduction in life expectancy (Figure 1).⁵

Numerous mechanisms have been hypothesized to account for the association between diabetes and cardiovascular risk, including increased inflammation, endothelial and platelet dysfunction, and autonomic dysregulation.⁶

Can we modify cardiovascular risk in patients with diabetes?

Although fasting blood glucose levels strongly correlate with future cardiovascular risk, whether lowering blood glucose levels with medications will reduce cardiovascular risk has been uncertain.³ Lowering glucose beyond what is current standard practice has not been shown to significantly improve cardiovascular outcomes or mortality rates, and it comes at the price of an increased risk of hypoglycemic events.

No macrovascular benefit from lowering hemoglobin A_1c beyond the standard of care

UKPDS.⁷ Launched in 1977, the United Kingdom Prospective Diabetes Study was designed to investigate whether intensive blood glucose control reduces the risk of macrovascular and microvascular complications in type 2 diabetes. The study randomized nearly 4,000 patients newly diagnosed with diabetes to intensive treatment (with a sulfonylurea or insulin to keep fasting blood glucose levels below 110 mg/dL) or to conventional treatment (with diet alone unless hyperglycemic symptoms or a fasting blood glucose more than 270 mg/dL arose) for 10 years.

Multivariate analysis from the overall study population revealed a direct correlation between hemoglobin A_1c levels and adverse cardiovascular events. Higher hemoglobin A_1c was associated with markedly more:

• Fatal and nonfatal myocardial infarctions (14% increased risk for every 1% rise in hemoglobin A_1c)
• Fatal and nonfatal strokes (12% increased risk per 1% rise in hemoglobin A_1c)
• Amputations or deaths from peripheral vascular disease (43% increase per 1% rise)
• Heart failure (16% increase per 1% rise).

While intensive therapy was associated with significant reductions in microvascular events (retinopathy and proteinuria), there was no significant difference in the incidence of major macrovascular events (myocardial infarction or stroke).

The mean hemoglobin A_1c level at the end of the study was about 8% in the standard-treatment group and about 7% in the intensive-treatment group. Were these levels low enough to yield a significant risk reduction? Since lower hemoglobin A_1c levels are associated with lower risk of myocardial infarction, it seemed reasonable to do further studies with more intensive treatment to further lower hemoglobin A_1c goals.

ADVANCE.⁸ The Action in Diabetes and Vascular Disease trial randomized more than 11,000 participants with type 2 diabetes to either usual care or intensive therapy with a goal of achieving a hemoglobin A_1c of 6.5% or less. During 5 years of follow-up, the usual-care group averaged a hemoglobin A_1c of 7.3%, compared with 6.5% in the intensive-treatment group.

No significant differences between the two groups were observed in the incidence of major macrovascular events, including myocardial infarction, stroke, or death from any cause. The intensive-treatment group had fewer major microvascular events, with most of the benefit being in the form of a lower incidence of proteinuria, and with no significant effect on retinopathy. Severe hypoglycemia, although uncommon, was more frequent in the intensive-treatment group.

ACCORD.⁹ The Action to Control Cardiovascular Risk in Diabetes trial went one step further. This trial randomized more than 10,000 patients with type 2 diabetes to receive either intensive therapy (targeting hemoglobin A_1c ≤ 6.0%) or standard therapy (hemoglobin A_1c 7.0%–7.9%). At 1 year, the mean hemoglobin A_1c levels were stable at 6.4% in the intensive-therapy group and 7.5% in the standard-therapy group.

The trial was stopped at 3.5 years because of a higher rate of death in the intensive-therapy group, with a hazard ratio of 1.22, predominantly from an increase in adverse cardiovascular events. The intensive-therapy group also had a significantly higher incidence of hypoglycemia.

VADT.¹⁰ The Veterans Affairs Diabetes Trial randomized 1,791 patients with type 2 diabetes who had a suboptimal response to conventional therapy to receive intensive therapy aimed at reducing hemoglobin A_1c by 1.5 percentage points or standard therapy. After a follow-up of 5.6 years, median hemoglobin A_1c levels were 8.4% in the standard-therapy group and 6.9% in the intensive-therapy group. No differences were found between the two groups in the incidence of major cardiovascular events, death, or microvascular complications, with the exception of a lower rate of progression of albuminuria in the intensive-therapy group. The rates of adverse events, primarily hypoglycemia, were higher in the intensive-therapy group.

Based on these negative trials and concern about potential harm with intensive glucose-lowering strategies, standard guidelines continue to recommend moderate glucose-lowering strategies for patients with diabetes. The guidelines broadly recommend targeting a hemoglobin A_1c of 7% or less while advocating a less ambitious goal of lower than 7.5% or 8.0% in older patients who may be prone to hypoglycemia.¹¹

STRATEGIES TO REDUCE CARDIOVASCULAR RISK IN DIABETES

While the incidence of diabetes mellitus has risen alarmingly, the incidence of cardiovascular complications of diabetes has declined over the years. Lowering blood glucose has not been the critical factor mediating this risk reduction. In addition to smoking cessation, proven measures that clearly reduce long-term cardiovascular risk in diabetes are blood pressure control and reduction in low-density lipoprotein cholesterol with statins.

Lower the blood pressure to less than 140 mm Hg

ADVANCE.¹² In the ADVANCE trial, in addition to being randomized to usual vs intensive glucose-lowering therapy, participants were also simultaneously randomized to receive either placebo or the combination of an angiotensin-converting enzyme inhibitor and a diuretic (ie, perindopril and indapamide). Blood pressure was reduced by a mean of 5.6 mm Hg systolic and 2.2 mm Hg diastolic in the active-treatment group. This moderate reduction in blood pressure was associated with an 18% relative risk reduction in death from cardiovascular disease and a 14% relative risk reduction in death from any cause.

The ACCORD trial¹³ lowered systolic blood pressure even more in the intensive-treatment group, with a target systolic blood pressure of less than 120 mm Hg compared with less than 140 mm Hg in the control group. Intensive therapy did not prove to significantly reduce the risk of major cardiovascular events and was associated with a significantly higher rate of serious adverse events.

Therefore, while antihypertensive therapy lowered the mortality rate in diabetic patients, lowering blood pressure beyond conventional blood pressure targets did not decrease the risk more. The latest hypertension treatment guidelines (from the eighth Joint National Committee) emphasize a blood pressure goal of 140/90 mm Hg or less in adults with diabetes.¹⁴

Prescribe a statin regardless of the baseline lipid level

The Collaborative Atorvastatin Diabetes Study (CARDS) randomized nearly 3,000 patients with type 2 diabetes mellitus and no history of cardiovascular disease to either atorvastatin 10 mg or placebo regardless of cholesterol status. The trial was terminated 2 years early because a prespecified efficacy end point had already been met: the treatment group experienced a markedly lower incidence of major cardiovascular events, including stroke.¹⁵

A large meta-analysis of randomized trials of statins noted a 9% reduction in all-cause mortality (relative risk [RR] 0.91, 99% confidence interval 0.82–1.01; P = .02) per mmol/L reduction in low-density lipoprotein cholesterol in patients with diabetes mellitus.¹⁶ Use of statins also led to significant reductions in rates of major coronary events (RR 0.78), coronary revascularization (RR 0.75), and stroke (RR 0.79).

The latest American College of Cardiology/American Heart Association guidelines endorse moderate-intensity or high-intensity statin treatment in patients with diabetes who are over age 40.¹⁷

Encourage smoking cessation

Smoking increases the lifetime risk of developing type 2 diabetes.¹⁸ It is also associated with premature development of microvascular and macrovascular complications of diabetes,¹⁹ and it leads to increased mortality risk in people with diabetes mellitus in a dose-dependent manner.²⁰ Therefore, smoking cessation remains paramount in reducing cardiovascular risk, and patients should be encouraged to quit as soon as possible.

Role of antiplatelet agents

Use of antiplatelet drugs such as aspirin for primary prevention of cardiovascular disease in patients with diabetes is controversial. Initial studies showed a potential reduction in the incidence of myocardial infarction in men and stroke in women with diabetes with low-dose aspirin.^21,22 Subsequent randomized trials and meta-analyses, however, yielded contrasting results, showing no benefit in cardiovascular risk reduction and potential risk of bleeding and other gastrointestinal adverse effects.^23,24

The US Food and Drug Administration (FDA) has not approved aspirin for primary prevention of cardiovascular disease in people who have no history of cardiovascular disease. In contrast, the American Heart Association and the American Diabetes Association endorse low-dose aspirin (75–162 mg/day) for adults with diabetes and no history of vascular disease who are at increased cardiovascular risk (estimated 10-year risk of events > 10%) and who are not at increased risk of bleeding.

In the absence of a clear consensus and given the lack of randomized data, the role of aspirin in patients with diabetes remains controversial.

WHAT IS THE ROLE OF STRESS TESTING IN ASYMPTOMATIC DIABETIC PATIENTS?

People with diabetes also have a high incidence of silent (asymptomatic) ischemia that potentially leads to worse outcomes.²⁵ Whether screening for silent ischemia improves outcomes in these patients is debatable.

The Detection of Anemia in Asymptomatic Diabetics (DIAD) trial randomized more than 1,000 asymptomatic diabetic participants to either screening for coronary artery disease with stress testing or no screening.²⁶ Over a 5-year follow-up, there was no significant difference in the incidence of myocardial infarction and death from cardiac causes.

The guidelines remain divided on this clinical conundrum. While the American Diabetes Association recommends against routine screening for coronary artery disease in asymptomatic patients with diabetes, the American College of Cardiology/American Heart Association guidelines recommend screening with radionuclide imaging in patients with diabetes and a high risk of coronary artery disease.²⁷

ROLE OF REVASCULARIZATION IN DIABETIC PATIENTS WITH STABLE CORONARY ARTERY DISEASE

Patients with coronary artery disease and diabetes fare worse than those without diabetes, despite revascularization by coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI).²⁸

The choice of CABG or PCI as the preferred revascularization strategy was recently studied in the Future Revascularization Evaluation in Patients With DM: Optimal Management of Multivessel Disease (FREEDOM) trial.²⁹ This study randomized 1,900 patients with diabetes and multivessel coronary artery disease to revascularization with PCI or CABG. After 5 years, there was a significantly lower rate of death and myocardial infarction with CABG than with PCI.

The role of revascularization in patients with diabetes and stable coronary artery disease has also been questioned. The Bypass Angioplasty Revascularization Investigation 2 DM (BARI-2D) randomized 2,368 patients with diabetes and stable coronary artery disease to undergo revascularization (PCI or CABG) or to receive intensive medical therapy alone.³⁰ At 5 years, there was no significant difference in the rates of death and major cardiovascular events between patients undergoing revascularization and those undergoing medical therapy alone. Subgroup analysis revealed a potential benefit with CABG over medical therapy in patients with more extensive coronary artery disease.³¹

CAN DIABETES THERAPY CAUSE HARM?

New diabetes drugs must show no cardiovascular harm

Several drugs that were approved purely on the basis of their potential to reduce blood glucose were reevaluated for impact on adverse cardiovascular outcomes.

Muraglitazar is a peroxisome proliferator-activated receptor agonist that was shown in phase 2 and 3 studies to dramatically lower triglyceride levels in a dose-dependent fashion while raising high-density lipoprotein levels and being neutral to low-density lipoprotein levels. It also lowers blood glucose. The FDA Advisory Committee voted to approve its use for type 2 diabetes based on phase 2 trial data. But soon after, a meta-analysis revealed that the drug was associated with more than twice the incidence of cardiovascular complications and death than standard therapy.³² Further development of this drug subsequently ceased.

A similar meta-analysis was performed on rosiglitazone, a drug that has been available since 1997 and had been used by millions of patients. Rosiglitazone was also found to be associated with a significantly increased risk of cardiovascular death, as well as death from all causes.³³

In light of these findings, the FDA in 2008 issued new guidelines to the diabetes drug development industry. Henceforth, new diabetes drugs must not only lower blood glucose, they must also be shown in a large clinical trial not to increase cardiovascular risk.

Current trials will provide critical information

Numerous trials are now under way to assess cardiovascular outcomes with promising new diabetes drugs. Tens of thousands of patients are involved in trials testing dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide-1 agonists, sodium-glucose-linked transporter-2 agents, and a GPR40 agonist. Because of the change in guidelines, results over the next decade should reveal much more about the impact of lowering blood glucose on heart disease than we learned in the previous century.

Two apparently neutral but clinically relevant trials recently examined cardiovascular outcomes associated with diabetes drugs.

EXAMINE.³⁴ The Examination of Cardiovascular Outcomes Study of Alogliptin Versus Standard of Care study randomized 5,380 patients with type 2 diabetes and a recent acute coronary syndrome event (acute myocardial infarction or unstable angina requiring hospitalization) to receive either alogliptin (a DPP-4 inhibitor) or placebo in addition to existing standard diabetes and cardiovascular therapy. Patients were followed for up to 40 months (median 18 months). Hemoglobin A_1c levels were significantly lower with alogliptin than with placebo, but the time to the primary end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was not significantly different between the two groups.

SAVOR.³⁵ The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with DM (SAVOR–TIMI 53) trial randomized more than 16,000 patients with established cardiovascular disease or multiple risk factors to either the DPP-4 inhibitor saxagliptin or placebo. The patients’ physicians were permitted to adjust all other medications, including standard diabetes medications. The median treatment period was just over 2 years. Similar to EXAMINE, this study found no difference between the two groups in the primary end point of cardiovascular death, myocardial infarction, or ischemic stroke, even though glycemic control was better in the saxagliptin group.

Thus, both drugs were shown not to increase cardiovascular risk, an FDA criterion for drug marketing and approval.

CONTROL MODIFIABLE RISK FACTORS

There has been an alarming rise in the incidence of diabetes and obesity throughout the world. Cardiovascular disease remains the leading cause of death in patients with diabetes. While elevated blood glucose in diabetic patients leads to increased cardiovascular risk, efforts to reduce blood glucose to euglycemic levels may not lead to a reduction in this risk and may even cause harm.

Success in cardiovascular risk reduction in addition to glucose-lowering remains the holy grail in the development of new diabetes drugs. But in the meantime, aggressive control of other modifiable risk factors such as hypertension, smoking, and hyperlipidemia remains critical to reducing cardiovascular risk in diabetic patients.

A 50-year-old man with hypertension presents to the internal medicine clinic. He has been an active smoker for 15 years and smokes 1 pack of cigarettes a day. He was recently diagnosed with type 2 diabetes mellitus after routine blood work revealed his hemoglobin A_1c level was elevated at 7.5%. He has no current complaints but is concerned about his future risk of a heart attack or stroke.

See related commentary

THE BURDEN OF DIABETES MELLITUS

The prevalence of diabetes mellitus in US adults (age > 20) has tripled during the last 30 years to 28.9 million, or 12% of the population in this age group.¹ Globally, 382 million people had a diagnosis of diabetes in 2013, and with the increasing prevalence of obesity and adoption of a Western diet, this number is expected to escalate to 592 million by 2035.²

HOW GREAT IS THE CARDIOVASCULAR RISK IN PEOPLE WITH DIABETES?

Seshasai SR, et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 2011; 364:829–841.Copyright 2011 Massachusetts Medical Society (MMS). Reprinted with permission from MMS.

Diabetes mellitus is linked to a twofold increase in the risk of adverse cardiovascular events even after adjusting for risk from hypertension and smoking.³ In early studies, diabetic people with no history of myocardial infarction were shown to have a lifetime risk of infarction similar to that in nondiabetic people who had already had an infarction,⁴ thus establishing diabetes as a “coronary artery disease equivalent.” Middle-aged men diagnosed with diabetes lose an average of 6 years of life and women lose 7 years compared with those without diabetes, with cardiovascular morbidity contributing to more than half of this reduction in life expectancy (Figure 1).⁵

Numerous mechanisms have been hypothesized to account for the association between diabetes and cardiovascular risk, including increased inflammation, endothelial and platelet dysfunction, and autonomic dysregulation.⁶

Can we modify cardiovascular risk in patients with diabetes?

Although fasting blood glucose levels strongly correlate with future cardiovascular risk, whether lowering blood glucose levels with medications will reduce cardiovascular risk has been uncertain.³ Lowering glucose beyond what is current standard practice has not been shown to significantly improve cardiovascular outcomes or mortality rates, and it comes at the price of an increased risk of hypoglycemic events.

No macrovascular benefit from lowering hemoglobin A_1c beyond the standard of care

UKPDS.⁷ Launched in 1977, the United Kingdom Prospective Diabetes Study was designed to investigate whether intensive blood glucose control reduces the risk of macrovascular and microvascular complications in type 2 diabetes. The study randomized nearly 4,000 patients newly diagnosed with diabetes to intensive treatment (with a sulfonylurea or insulin to keep fasting blood glucose levels below 110 mg/dL) or to conventional treatment (with diet alone unless hyperglycemic symptoms or a fasting blood glucose more than 270 mg/dL arose) for 10 years.

Multivariate analysis from the overall study population revealed a direct correlation between hemoglobin A_1c levels and adverse cardiovascular events. Higher hemoglobin A_1c was associated with markedly more:

• Fatal and nonfatal myocardial infarctions (14% increased risk for every 1% rise in hemoglobin A_1c)
• Fatal and nonfatal strokes (12% increased risk per 1% rise in hemoglobin A_1c)
• Amputations or deaths from peripheral vascular disease (43% increase per 1% rise)
• Heart failure (16% increase per 1% rise).

While intensive therapy was associated with significant reductions in microvascular events (retinopathy and proteinuria), there was no significant difference in the incidence of major macrovascular events (myocardial infarction or stroke).

The mean hemoglobin A_1c level at the end of the study was about 8% in the standard-treatment group and about 7% in the intensive-treatment group. Were these levels low enough to yield a significant risk reduction? Since lower hemoglobin A_1c levels are associated with lower risk of myocardial infarction, it seemed reasonable to do further studies with more intensive treatment to further lower hemoglobin A_1c goals.

ADVANCE.⁸ The Action in Diabetes and Vascular Disease trial randomized more than 11,000 participants with type 2 diabetes to either usual care or intensive therapy with a goal of achieving a hemoglobin A_1c of 6.5% or less. During 5 years of follow-up, the usual-care group averaged a hemoglobin A_1c of 7.3%, compared with 6.5% in the intensive-treatment group.

No significant differences between the two groups were observed in the incidence of major macrovascular events, including myocardial infarction, stroke, or death from any cause. The intensive-treatment group had fewer major microvascular events, with most of the benefit being in the form of a lower incidence of proteinuria, and with no significant effect on retinopathy. Severe hypoglycemia, although uncommon, was more frequent in the intensive-treatment group.

ACCORD.⁹ The Action to Control Cardiovascular Risk in Diabetes trial went one step further. This trial randomized more than 10,000 patients with type 2 diabetes to receive either intensive therapy (targeting hemoglobin A_1c ≤ 6.0%) or standard therapy (hemoglobin A_1c 7.0%–7.9%). At 1 year, the mean hemoglobin A_1c levels were stable at 6.4% in the intensive-therapy group and 7.5% in the standard-therapy group.

The trial was stopped at 3.5 years because of a higher rate of death in the intensive-therapy group, with a hazard ratio of 1.22, predominantly from an increase in adverse cardiovascular events. The intensive-therapy group also had a significantly higher incidence of hypoglycemia.

VADT.¹⁰ The Veterans Affairs Diabetes Trial randomized 1,791 patients with type 2 diabetes who had a suboptimal response to conventional therapy to receive intensive therapy aimed at reducing hemoglobin A_1c by 1.5 percentage points or standard therapy. After a follow-up of 5.6 years, median hemoglobin A_1c levels were 8.4% in the standard-therapy group and 6.9% in the intensive-therapy group. No differences were found between the two groups in the incidence of major cardiovascular events, death, or microvascular complications, with the exception of a lower rate of progression of albuminuria in the intensive-therapy group. The rates of adverse events, primarily hypoglycemia, were higher in the intensive-therapy group.

Based on these negative trials and concern about potential harm with intensive glucose-lowering strategies, standard guidelines continue to recommend moderate glucose-lowering strategies for patients with diabetes. The guidelines broadly recommend targeting a hemoglobin A_1c of 7% or less while advocating a less ambitious goal of lower than 7.5% or 8.0% in older patients who may be prone to hypoglycemia.¹¹

STRATEGIES TO REDUCE CARDIOVASCULAR RISK IN DIABETES

While the incidence of diabetes mellitus has risen alarmingly, the incidence of cardiovascular complications of diabetes has declined over the years. Lowering blood glucose has not been the critical factor mediating this risk reduction. In addition to smoking cessation, proven measures that clearly reduce long-term cardiovascular risk in diabetes are blood pressure control and reduction in low-density lipoprotein cholesterol with statins.

Lower the blood pressure to less than 140 mm Hg

ADVANCE.¹² In the ADVANCE trial, in addition to being randomized to usual vs intensive glucose-lowering therapy, participants were also simultaneously randomized to receive either placebo or the combination of an angiotensin-converting enzyme inhibitor and a diuretic (ie, perindopril and indapamide). Blood pressure was reduced by a mean of 5.6 mm Hg systolic and 2.2 mm Hg diastolic in the active-treatment group. This moderate reduction in blood pressure was associated with an 18% relative risk reduction in death from cardiovascular disease and a 14% relative risk reduction in death from any cause.

The ACCORD trial¹³ lowered systolic blood pressure even more in the intensive-treatment group, with a target systolic blood pressure of less than 120 mm Hg compared with less than 140 mm Hg in the control group. Intensive therapy did not prove to significantly reduce the risk of major cardiovascular events and was associated with a significantly higher rate of serious adverse events.

Therefore, while antihypertensive therapy lowered the mortality rate in diabetic patients, lowering blood pressure beyond conventional blood pressure targets did not decrease the risk more. The latest hypertension treatment guidelines (from the eighth Joint National Committee) emphasize a blood pressure goal of 140/90 mm Hg or less in adults with diabetes.¹⁴

Prescribe a statin regardless of the baseline lipid level

The Collaborative Atorvastatin Diabetes Study (CARDS) randomized nearly 3,000 patients with type 2 diabetes mellitus and no history of cardiovascular disease to either atorvastatin 10 mg or placebo regardless of cholesterol status. The trial was terminated 2 years early because a prespecified efficacy end point had already been met: the treatment group experienced a markedly lower incidence of major cardiovascular events, including stroke.¹⁵

A large meta-analysis of randomized trials of statins noted a 9% reduction in all-cause mortality (relative risk [RR] 0.91, 99% confidence interval 0.82–1.01; P = .02) per mmol/L reduction in low-density lipoprotein cholesterol in patients with diabetes mellitus.¹⁶ Use of statins also led to significant reductions in rates of major coronary events (RR 0.78), coronary revascularization (RR 0.75), and stroke (RR 0.79).

The latest American College of Cardiology/American Heart Association guidelines endorse moderate-intensity or high-intensity statin treatment in patients with diabetes who are over age 40.¹⁷

Encourage smoking cessation

Smoking increases the lifetime risk of developing type 2 diabetes.¹⁸ It is also associated with premature development of microvascular and macrovascular complications of diabetes,¹⁹ and it leads to increased mortality risk in people with diabetes mellitus in a dose-dependent manner.²⁰ Therefore, smoking cessation remains paramount in reducing cardiovascular risk, and patients should be encouraged to quit as soon as possible.

Role of antiplatelet agents

Use of antiplatelet drugs such as aspirin for primary prevention of cardiovascular disease in patients with diabetes is controversial. Initial studies showed a potential reduction in the incidence of myocardial infarction in men and stroke in women with diabetes with low-dose aspirin.^21,22 Subsequent randomized trials and meta-analyses, however, yielded contrasting results, showing no benefit in cardiovascular risk reduction and potential risk of bleeding and other gastrointestinal adverse effects.^23,24

The US Food and Drug Administration (FDA) has not approved aspirin for primary prevention of cardiovascular disease in people who have no history of cardiovascular disease. In contrast, the American Heart Association and the American Diabetes Association endorse low-dose aspirin (75–162 mg/day) for adults with diabetes and no history of vascular disease who are at increased cardiovascular risk (estimated 10-year risk of events > 10%) and who are not at increased risk of bleeding.

In the absence of a clear consensus and given the lack of randomized data, the role of aspirin in patients with diabetes remains controversial.

WHAT IS THE ROLE OF STRESS TESTING IN ASYMPTOMATIC DIABETIC PATIENTS?

People with diabetes also have a high incidence of silent (asymptomatic) ischemia that potentially leads to worse outcomes.²⁵ Whether screening for silent ischemia improves outcomes in these patients is debatable.

The Detection of Anemia in Asymptomatic Diabetics (DIAD) trial randomized more than 1,000 asymptomatic diabetic participants to either screening for coronary artery disease with stress testing or no screening.²⁶ Over a 5-year follow-up, there was no significant difference in the incidence of myocardial infarction and death from cardiac causes.

The guidelines remain divided on this clinical conundrum. While the American Diabetes Association recommends against routine screening for coronary artery disease in asymptomatic patients with diabetes, the American College of Cardiology/American Heart Association guidelines recommend screening with radionuclide imaging in patients with diabetes and a high risk of coronary artery disease.²⁷

ROLE OF REVASCULARIZATION IN DIABETIC PATIENTS WITH STABLE CORONARY ARTERY DISEASE

Patients with coronary artery disease and diabetes fare worse than those without diabetes, despite revascularization by coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI).²⁸

The choice of CABG or PCI as the preferred revascularization strategy was recently studied in the Future Revascularization Evaluation in Patients With DM: Optimal Management of Multivessel Disease (FREEDOM) trial.²⁹ This study randomized 1,900 patients with diabetes and multivessel coronary artery disease to revascularization with PCI or CABG. After 5 years, there was a significantly lower rate of death and myocardial infarction with CABG than with PCI.

The role of revascularization in patients with diabetes and stable coronary artery disease has also been questioned. The Bypass Angioplasty Revascularization Investigation 2 DM (BARI-2D) randomized 2,368 patients with diabetes and stable coronary artery disease to undergo revascularization (PCI or CABG) or to receive intensive medical therapy alone.³⁰ At 5 years, there was no significant difference in the rates of death and major cardiovascular events between patients undergoing revascularization and those undergoing medical therapy alone. Subgroup analysis revealed a potential benefit with CABG over medical therapy in patients with more extensive coronary artery disease.³¹

CAN DIABETES THERAPY CAUSE HARM?

New diabetes drugs must show no cardiovascular harm

Several drugs that were approved purely on the basis of their potential to reduce blood glucose were reevaluated for impact on adverse cardiovascular outcomes.

Muraglitazar is a peroxisome proliferator-activated receptor agonist that was shown in phase 2 and 3 studies to dramatically lower triglyceride levels in a dose-dependent fashion while raising high-density lipoprotein levels and being neutral to low-density lipoprotein levels. It also lowers blood glucose. The FDA Advisory Committee voted to approve its use for type 2 diabetes based on phase 2 trial data. But soon after, a meta-analysis revealed that the drug was associated with more than twice the incidence of cardiovascular complications and death than standard therapy.³² Further development of this drug subsequently ceased.

A similar meta-analysis was performed on rosiglitazone, a drug that has been available since 1997 and had been used by millions of patients. Rosiglitazone was also found to be associated with a significantly increased risk of cardiovascular death, as well as death from all causes.³³

In light of these findings, the FDA in 2008 issued new guidelines to the diabetes drug development industry. Henceforth, new diabetes drugs must not only lower blood glucose, they must also be shown in a large clinical trial not to increase cardiovascular risk.

Current trials will provide critical information

Numerous trials are now under way to assess cardiovascular outcomes with promising new diabetes drugs. Tens of thousands of patients are involved in trials testing dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide-1 agonists, sodium-glucose-linked transporter-2 agents, and a GPR40 agonist. Because of the change in guidelines, results over the next decade should reveal much more about the impact of lowering blood glucose on heart disease than we learned in the previous century.

Two apparently neutral but clinically relevant trials recently examined cardiovascular outcomes associated with diabetes drugs.

EXAMINE.³⁴ The Examination of Cardiovascular Outcomes Study of Alogliptin Versus Standard of Care study randomized 5,380 patients with type 2 diabetes and a recent acute coronary syndrome event (acute myocardial infarction or unstable angina requiring hospitalization) to receive either alogliptin (a DPP-4 inhibitor) or placebo in addition to existing standard diabetes and cardiovascular therapy. Patients were followed for up to 40 months (median 18 months). Hemoglobin A_1c levels were significantly lower with alogliptin than with placebo, but the time to the primary end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was not significantly different between the two groups.

SAVOR.³⁵ The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with DM (SAVOR–TIMI 53) trial randomized more than 16,000 patients with established cardiovascular disease or multiple risk factors to either the DPP-4 inhibitor saxagliptin or placebo. The patients’ physicians were permitted to adjust all other medications, including standard diabetes medications. The median treatment period was just over 2 years. Similar to EXAMINE, this study found no difference between the two groups in the primary end point of cardiovascular death, myocardial infarction, or ischemic stroke, even though glycemic control was better in the saxagliptin group.

Thus, both drugs were shown not to increase cardiovascular risk, an FDA criterion for drug marketing and approval.

CONTROL MODIFIABLE RISK FACTORS

There has been an alarming rise in the incidence of diabetes and obesity throughout the world. Cardiovascular disease remains the leading cause of death in patients with diabetes. While elevated blood glucose in diabetic patients leads to increased cardiovascular risk, efforts to reduce blood glucose to euglycemic levels may not lead to a reduction in this risk and may even cause harm.

Success in cardiovascular risk reduction in addition to glucose-lowering remains the holy grail in the development of new diabetes drugs. But in the meantime, aggressive control of other modifiable risk factors such as hypertension, smoking, and hyperlipidemia remains critical to reducing cardiovascular risk in diabetic patients.

A 50-year-old man with hypertension presents to the internal medicine clinic. He has been an active smoker for 15 years and smokes 1 pack of cigarettes a day. He was recently diagnosed with type 2 diabetes mellitus after routine blood work revealed his hemoglobin A_1c level was elevated at 7.5%. He has no current complaints but is concerned about his future risk of a heart attack or stroke.

See related commentary

THE BURDEN OF DIABETES MELLITUS

The prevalence of diabetes mellitus in US adults (age > 20) has tripled during the last 30 years to 28.9 million, or 12% of the population in this age group.¹ Globally, 382 million people had a diagnosis of diabetes in 2013, and with the increasing prevalence of obesity and adoption of a Western diet, this number is expected to escalate to 592 million by 2035.²

HOW GREAT IS THE CARDIOVASCULAR RISK IN PEOPLE WITH DIABETES?

Seshasai SR, et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 2011; 364:829–841.Copyright 2011 Massachusetts Medical Society (MMS). Reprinted with permission from MMS.

Diabetes mellitus is linked to a twofold increase in the risk of adverse cardiovascular events even after adjusting for risk from hypertension and smoking.³ In early studies, diabetic people with no history of myocardial infarction were shown to have a lifetime risk of infarction similar to that in nondiabetic people who had already had an infarction,⁴ thus establishing diabetes as a “coronary artery disease equivalent.” Middle-aged men diagnosed with diabetes lose an average of 6 years of life and women lose 7 years compared with those without diabetes, with cardiovascular morbidity contributing to more than half of this reduction in life expectancy (Figure 1).⁵

Numerous mechanisms have been hypothesized to account for the association between diabetes and cardiovascular risk, including increased inflammation, endothelial and platelet dysfunction, and autonomic dysregulation.⁶

Can we modify cardiovascular risk in patients with diabetes?

Although fasting blood glucose levels strongly correlate with future cardiovascular risk, whether lowering blood glucose levels with medications will reduce cardiovascular risk has been uncertain.³ Lowering glucose beyond what is current standard practice has not been shown to significantly improve cardiovascular outcomes or mortality rates, and it comes at the price of an increased risk of hypoglycemic events.

No macrovascular benefit from lowering hemoglobin A_1c beyond the standard of care

UKPDS.⁷ Launched in 1977, the United Kingdom Prospective Diabetes Study was designed to investigate whether intensive blood glucose control reduces the risk of macrovascular and microvascular complications in type 2 diabetes. The study randomized nearly 4,000 patients newly diagnosed with diabetes to intensive treatment (with a sulfonylurea or insulin to keep fasting blood glucose levels below 110 mg/dL) or to conventional treatment (with diet alone unless hyperglycemic symptoms or a fasting blood glucose more than 270 mg/dL arose) for 10 years.

Multivariate analysis from the overall study population revealed a direct correlation between hemoglobin A_1c levels and adverse cardiovascular events. Higher hemoglobin A_1c was associated with markedly more:

• Fatal and nonfatal myocardial infarctions (14% increased risk for every 1% rise in hemoglobin A_1c)
• Fatal and nonfatal strokes (12% increased risk per 1% rise in hemoglobin A_1c)
• Amputations or deaths from peripheral vascular disease (43% increase per 1% rise)
• Heart failure (16% increase per 1% rise).

While intensive therapy was associated with significant reductions in microvascular events (retinopathy and proteinuria), there was no significant difference in the incidence of major macrovascular events (myocardial infarction or stroke).

The mean hemoglobin A_1c level at the end of the study was about 8% in the standard-treatment group and about 7% in the intensive-treatment group. Were these levels low enough to yield a significant risk reduction? Since lower hemoglobin A_1c levels are associated with lower risk of myocardial infarction, it seemed reasonable to do further studies with more intensive treatment to further lower hemoglobin A_1c goals.

ADVANCE.⁸ The Action in Diabetes and Vascular Disease trial randomized more than 11,000 participants with type 2 diabetes to either usual care or intensive therapy with a goal of achieving a hemoglobin A_1c of 6.5% or less. During 5 years of follow-up, the usual-care group averaged a hemoglobin A_1c of 7.3%, compared with 6.5% in the intensive-treatment group.

No significant differences between the two groups were observed in the incidence of major macrovascular events, including myocardial infarction, stroke, or death from any cause. The intensive-treatment group had fewer major microvascular events, with most of the benefit being in the form of a lower incidence of proteinuria, and with no significant effect on retinopathy. Severe hypoglycemia, although uncommon, was more frequent in the intensive-treatment group.

ACCORD.⁹ The Action to Control Cardiovascular Risk in Diabetes trial went one step further. This trial randomized more than 10,000 patients with type 2 diabetes to receive either intensive therapy (targeting hemoglobin A_1c ≤ 6.0%) or standard therapy (hemoglobin A_1c 7.0%–7.9%). At 1 year, the mean hemoglobin A_1c levels were stable at 6.4% in the intensive-therapy group and 7.5% in the standard-therapy group.

The trial was stopped at 3.5 years because of a higher rate of death in the intensive-therapy group, with a hazard ratio of 1.22, predominantly from an increase in adverse cardiovascular events. The intensive-therapy group also had a significantly higher incidence of hypoglycemia.

VADT.¹⁰ The Veterans Affairs Diabetes Trial randomized 1,791 patients with type 2 diabetes who had a suboptimal response to conventional therapy to receive intensive therapy aimed at reducing hemoglobin A_1c by 1.5 percentage points or standard therapy. After a follow-up of 5.6 years, median hemoglobin A_1c levels were 8.4% in the standard-therapy group and 6.9% in the intensive-therapy group. No differences were found between the two groups in the incidence of major cardiovascular events, death, or microvascular complications, with the exception of a lower rate of progression of albuminuria in the intensive-therapy group. The rates of adverse events, primarily hypoglycemia, were higher in the intensive-therapy group.

Based on these negative trials and concern about potential harm with intensive glucose-lowering strategies, standard guidelines continue to recommend moderate glucose-lowering strategies for patients with diabetes. The guidelines broadly recommend targeting a hemoglobin A_1c of 7% or less while advocating a less ambitious goal of lower than 7.5% or 8.0% in older patients who may be prone to hypoglycemia.¹¹

STRATEGIES TO REDUCE CARDIOVASCULAR RISK IN DIABETES

While the incidence of diabetes mellitus has risen alarmingly, the incidence of cardiovascular complications of diabetes has declined over the years. Lowering blood glucose has not been the critical factor mediating this risk reduction. In addition to smoking cessation, proven measures that clearly reduce long-term cardiovascular risk in diabetes are blood pressure control and reduction in low-density lipoprotein cholesterol with statins.

Lower the blood pressure to less than 140 mm Hg

ADVANCE.¹² In the ADVANCE trial, in addition to being randomized to usual vs intensive glucose-lowering therapy, participants were also simultaneously randomized to receive either placebo or the combination of an angiotensin-converting enzyme inhibitor and a diuretic (ie, perindopril and indapamide). Blood pressure was reduced by a mean of 5.6 mm Hg systolic and 2.2 mm Hg diastolic in the active-treatment group. This moderate reduction in blood pressure was associated with an 18% relative risk reduction in death from cardiovascular disease and a 14% relative risk reduction in death from any cause.

The ACCORD trial¹³ lowered systolic blood pressure even more in the intensive-treatment group, with a target systolic blood pressure of less than 120 mm Hg compared with less than 140 mm Hg in the control group. Intensive therapy did not prove to significantly reduce the risk of major cardiovascular events and was associated with a significantly higher rate of serious adverse events.

Therefore, while antihypertensive therapy lowered the mortality rate in diabetic patients, lowering blood pressure beyond conventional blood pressure targets did not decrease the risk more. The latest hypertension treatment guidelines (from the eighth Joint National Committee) emphasize a blood pressure goal of 140/90 mm Hg or less in adults with diabetes.¹⁴

Prescribe a statin regardless of the baseline lipid level

The Collaborative Atorvastatin Diabetes Study (CARDS) randomized nearly 3,000 patients with type 2 diabetes mellitus and no history of cardiovascular disease to either atorvastatin 10 mg or placebo regardless of cholesterol status. The trial was terminated 2 years early because a prespecified efficacy end point had already been met: the treatment group experienced a markedly lower incidence of major cardiovascular events, including stroke.¹⁵

A large meta-analysis of randomized trials of statins noted a 9% reduction in all-cause mortality (relative risk [RR] 0.91, 99% confidence interval 0.82–1.01; P = .02) per mmol/L reduction in low-density lipoprotein cholesterol in patients with diabetes mellitus.¹⁶ Use of statins also led to significant reductions in rates of major coronary events (RR 0.78), coronary revascularization (RR 0.75), and stroke (RR 0.79).

The latest American College of Cardiology/American Heart Association guidelines endorse moderate-intensity or high-intensity statin treatment in patients with diabetes who are over age 40.¹⁷

Encourage smoking cessation

Smoking increases the lifetime risk of developing type 2 diabetes.¹⁸ It is also associated with premature development of microvascular and macrovascular complications of diabetes,¹⁹ and it leads to increased mortality risk in people with diabetes mellitus in a dose-dependent manner.²⁰ Therefore, smoking cessation remains paramount in reducing cardiovascular risk, and patients should be encouraged to quit as soon as possible.

Role of antiplatelet agents

Use of antiplatelet drugs such as aspirin for primary prevention of cardiovascular disease in patients with diabetes is controversial. Initial studies showed a potential reduction in the incidence of myocardial infarction in men and stroke in women with diabetes with low-dose aspirin.^21,22 Subsequent randomized trials and meta-analyses, however, yielded contrasting results, showing no benefit in cardiovascular risk reduction and potential risk of bleeding and other gastrointestinal adverse effects.^23,24

The US Food and Drug Administration (FDA) has not approved aspirin for primary prevention of cardiovascular disease in people who have no history of cardiovascular disease. In contrast, the American Heart Association and the American Diabetes Association endorse low-dose aspirin (75–162 mg/day) for adults with diabetes and no history of vascular disease who are at increased cardiovascular risk (estimated 10-year risk of events > 10%) and who are not at increased risk of bleeding.

In the absence of a clear consensus and given the lack of randomized data, the role of aspirin in patients with diabetes remains controversial.

WHAT IS THE ROLE OF STRESS TESTING IN ASYMPTOMATIC DIABETIC PATIENTS?

People with diabetes also have a high incidence of silent (asymptomatic) ischemia that potentially leads to worse outcomes.²⁵ Whether screening for silent ischemia improves outcomes in these patients is debatable.

The Detection of Anemia in Asymptomatic Diabetics (DIAD) trial randomized more than 1,000 asymptomatic diabetic participants to either screening for coronary artery disease with stress testing or no screening.²⁶ Over a 5-year follow-up, there was no significant difference in the incidence of myocardial infarction and death from cardiac causes.

The guidelines remain divided on this clinical conundrum. While the American Diabetes Association recommends against routine screening for coronary artery disease in asymptomatic patients with diabetes, the American College of Cardiology/American Heart Association guidelines recommend screening with radionuclide imaging in patients with diabetes and a high risk of coronary artery disease.²⁷

ROLE OF REVASCULARIZATION IN DIABETIC PATIENTS WITH STABLE CORONARY ARTERY DISEASE

Patients with coronary artery disease and diabetes fare worse than those without diabetes, despite revascularization by coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI).²⁸

The choice of CABG or PCI as the preferred revascularization strategy was recently studied in the Future Revascularization Evaluation in Patients With DM: Optimal Management of Multivessel Disease (FREEDOM) trial.²⁹ This study randomized 1,900 patients with diabetes and multivessel coronary artery disease to revascularization with PCI or CABG. After 5 years, there was a significantly lower rate of death and myocardial infarction with CABG than with PCI.

The role of revascularization in patients with diabetes and stable coronary artery disease has also been questioned. The Bypass Angioplasty Revascularization Investigation 2 DM (BARI-2D) randomized 2,368 patients with diabetes and stable coronary artery disease to undergo revascularization (PCI or CABG) or to receive intensive medical therapy alone.³⁰ At 5 years, there was no significant difference in the rates of death and major cardiovascular events between patients undergoing revascularization and those undergoing medical therapy alone. Subgroup analysis revealed a potential benefit with CABG over medical therapy in patients with more extensive coronary artery disease.³¹

CAN DIABETES THERAPY CAUSE HARM?

New diabetes drugs must show no cardiovascular harm

Several drugs that were approved purely on the basis of their potential to reduce blood glucose were reevaluated for impact on adverse cardiovascular outcomes.

Muraglitazar is a peroxisome proliferator-activated receptor agonist that was shown in phase 2 and 3 studies to dramatically lower triglyceride levels in a dose-dependent fashion while raising high-density lipoprotein levels and being neutral to low-density lipoprotein levels. It also lowers blood glucose. The FDA Advisory Committee voted to approve its use for type 2 diabetes based on phase 2 trial data. But soon after, a meta-analysis revealed that the drug was associated with more than twice the incidence of cardiovascular complications and death than standard therapy.³² Further development of this drug subsequently ceased.

A similar meta-analysis was performed on rosiglitazone, a drug that has been available since 1997 and had been used by millions of patients. Rosiglitazone was also found to be associated with a significantly increased risk of cardiovascular death, as well as death from all causes.³³

In light of these findings, the FDA in 2008 issued new guidelines to the diabetes drug development industry. Henceforth, new diabetes drugs must not only lower blood glucose, they must also be shown in a large clinical trial not to increase cardiovascular risk.

Current trials will provide critical information

Numerous trials are now under way to assess cardiovascular outcomes with promising new diabetes drugs. Tens of thousands of patients are involved in trials testing dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide-1 agonists, sodium-glucose-linked transporter-2 agents, and a GPR40 agonist. Because of the change in guidelines, results over the next decade should reveal much more about the impact of lowering blood glucose on heart disease than we learned in the previous century.

Two apparently neutral but clinically relevant trials recently examined cardiovascular outcomes associated with diabetes drugs.

EXAMINE.³⁴ The Examination of Cardiovascular Outcomes Study of Alogliptin Versus Standard of Care study randomized 5,380 patients with type 2 diabetes and a recent acute coronary syndrome event (acute myocardial infarction or unstable angina requiring hospitalization) to receive either alogliptin (a DPP-4 inhibitor) or placebo in addition to existing standard diabetes and cardiovascular therapy. Patients were followed for up to 40 months (median 18 months). Hemoglobin A_1c levels were significantly lower with alogliptin than with placebo, but the time to the primary end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was not significantly different between the two groups.

SAVOR.³⁵ The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with DM (SAVOR–TIMI 53) trial randomized more than 16,000 patients with established cardiovascular disease or multiple risk factors to either the DPP-4 inhibitor saxagliptin or placebo. The patients’ physicians were permitted to adjust all other medications, including standard diabetes medications. The median treatment period was just over 2 years. Similar to EXAMINE, this study found no difference between the two groups in the primary end point of cardiovascular death, myocardial infarction, or ischemic stroke, even though glycemic control was better in the saxagliptin group.

Thus, both drugs were shown not to increase cardiovascular risk, an FDA criterion for drug marketing and approval.

CONTROL MODIFIABLE RISK FACTORS

There has been an alarming rise in the incidence of diabetes and obesity throughout the world. Cardiovascular disease remains the leading cause of death in patients with diabetes. While elevated blood glucose in diabetic patients leads to increased cardiovascular risk, efforts to reduce blood glucose to euglycemic levels may not lead to a reduction in this risk and may even cause harm.

Success in cardiovascular risk reduction in addition to glucose-lowering remains the holy grail in the development of new diabetes drugs. But in the meantime, aggressive control of other modifiable risk factors such as hypertension, smoking, and hyperlipidemia remains critical to reducing cardiovascular risk in diabetic patients.

Diabetes mellitus and its management have become the center of controversy in recent years. More emphasis is being placed on the potential for adverse cardiovascular outcomes with more aggressive glycemic control as well as on the potential for adverse cardiovascular events with newer antidiabetic therapies, and less on the importance of glycemic control, particularly early in the disease course.

See related article

Although it is important to take new data into consideration when managing diabetes, it appears that the results of recent clinical trials are being misinterpreted and incorrectly applied to the wrong patient populations, and in the process, the results of older landmark clinical trials are being neglected. Inadequate glycemic control not only plays a role in cardiovascular risk, it also remains the leading cause of blindness, kidney failure, and nontraumatic lower-limb amputations in the United States.¹

Although we need to recognize the potential for adverse cardiovascular outcomes with diabetes and its management, we cannot lose sight of the big picture—ie, that inadequate glycemic control confers both microvascular and macrovascular risk, and that the available data show that restoring near-euglycemia in patients with diabetes considerably reduces the risk of microvascular and macrovascular complications.

Several recently published clinical trials—the Action to Control Cardiovascular Risk in Diabetes (ACCORD),² the Veterans Affairs Diabetes Trial (VADT),³ and the Action in Diabetes and Vascular Disease (ADVANCE)⁴—failed to demonstrate improved cardiovascular outcomes with improved glycemic control. However, we should not take this to mean that glycemic control is unimportant.

In this article, we will discuss why the results of these recent clinical trials are not valid for the general population of patients with diabetes. We will review evidence from landmark clinical trials that clearly demonstrates that better glycemic control reduces both microvascular and macrovascular complications of diabetes (the “glucose hypothesis”). We contend that excellent glycemic control clearly decreases the microvascular complications of diabetes, and that results from long-term follow-up studies in both type 1 and type 2 diabetes show reduced rates of heart attack and stroke in patients treated intensively earlier in the course of their disease.^5,6

EVIDENCE FOR THE GLUCOSE HYPOTHESIS

Diabetes Control and Complications Trial

The first major trial demonstrating that improved glycemic control provides benefit was the Diabetes Control and Complications Trial (DCCT).⁷ This study enrolled 1,441 patients with insulin-dependent diabetes mellitus, 726 of whom had no retinopathy at baseline (the primary-prevention cohort) and 715 of whom had mild retinopathy (the secondary-intervention cohort).

Patients were randomly assigned to intensive therapy (three or more insulin injections per day or an insulin pump) or to conventional therapy with one or two daily insulin injections. They were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly.

During the study, the hemoglobin A_1c level averaged 9% in the control group and 7% in the intensively treated group. The cumulative incidence of retinopathy was defined as a change of three steps or more on fundus photography that was sustained over a 6-month period.

Effect on retinopathy. At study completion, the cumulative incidence of retinopathy in the intensive-therapy group was approximately 50% less than in the conventional-therapy group. Intensive therapy reduced the adjusted mean risk of retinopathy by 76% (95% confidence interval [CI] 62%–85%) in the primary-prevention cohort. In the secondary-prevention cohort, intensive therapy reduced the average risk of progression by 54% (95% CI 39%–66%). Intensive therapy reduced the adjusted risk of proliferative or severe nonproliferative retinopathy by 47% (P = .011) and that of treatment with photocoagulation by 56% (P = .002).

Effect on nephropathy. Intensive therapy reduced the mean adjusted risk of microalbuminuria by 34% (P = .04) in the primary-prevention cohort and by 43% (P = .001) in the secondary-intervention cohort. The risk of macroalbuminuria was reduced by 56% (P = .01) in the secondary-intervention cohort.

Effect on neuropathy. In the patients in the primary-prevention cohort who did not have neuropathy at baseline, intensive therapy reduced the incidence of neuropathy at 5 years by 69% (to 3%, vs 10% in the conventional-therapy group; P = .006). Similarly, in the secondary-intervention cohort, intensive therapy reduced the incidence of clinical neuropathy at 5 years by 57% (to 7%, vs 16%; P < .001).

Effect on macrovascular events. In the initial trial, a nonsignificant 41% reduction in combined cardiovascular and peripheral vascular disease events was observed.

DCCT long-term follow-up

After DCCT concluded, the control and treatment groups’ hemoglobin A_1c levels converged to approximately 8%. The two groups were then followed to determine the long-term effects of their prior separation of glycemic levels on micro- and macrovascular out comes.⁵ More than 90% of the original DCCT patients were followed for a mean of 17 years.

Intensive treatment reduced the risk of any cardiovascular disease event by 42% (95% CI 9%–63%; P = .02) and the risk of nonfatal myocardial infarction, stroke, or death from cardiovascular disease by 57% (95% CI 12%– 79%; P = .02). This result was observed despite separation of glucose control in the two groups only for the first 6.5 years. This beneficial effect of intensive early glycemic control has been termed metabolic memory.

United Kingdom Prospective Diabetes Study

A second major trial, the United Kingdom Prospective Diabetes Study (UKPDS),⁸ assessed the effect of excellent diabetes control on diabetes complications in patients with type 2 diabetes. A total of 3,867 patients newly diagnosed with type 2 diabetes, median age 54, who after 3 months of diet treatment had mean fasting plasma glucose concentrations of 110 to 270 mg/dL, were randomly assigned to an intensive policy (with a sulfonylurea or insulin or, if overweight, metformin) or a conventional policy with diet. The aim in the intensive group was a fasting plasma glucose less than 108 mg/dL. In the conventional group, the aim was the best achievable fasting plasma glucose with diet alone; drugs were added only if there were hyperglycemic symptoms or a fasting plasma glucose greater than 270 mg/dL.

Over 10 years, the median hemoglobin A_1c level was 7.0% (interquartile range 6.2%–8.2%) in the intensive group compared with 7.9% (6.9%–8.8%) in the conventional group. Compared with the conventional group, the risk of any diabetes-related end point was 12% lower in the intensive group (95% CI 1%–21%, P = .029), the risk of any diabetes-related death was 10% lower (−11% to 27%, P = .34), and the rate of all-cause mortality was 6% lower (−10% to 20%, P = .44). Most of the reduction in risk of any diabetes-related end point was from a 25% risk reduction (95% CI 7%–40%, P = .0099) in microvascular end points, including the need for retinal photocoagulation.

UKPDS long-term follow-up

In 2008, Holman et al published the results of long-term follow-up of patients included in the UKPDS.⁶ In posttrial monitoring, 3,277 patients were asked to attend annual UKPDS clinics for 5 years, but no attempts were made to maintain their previously assigned therapies. Annual questionnaires were used to follow patients who were unable to attend the clinics, and all patients in years 6 to 10 were assessed through questionnaires.

Between-group differences in hemoglobin A_1c levels were lost after the first year. However, in the sulfonylurea-insulin group, relative reductions in risk persisted at 10 years for any diabetes-related end point (9%, P = .04) and microvascular disease (24%, P = .001), while risk reductions for myocardial infarction (15%, P = .01) and death from any cause (13%, P = .007) emerged over time as more events occurred. In the metformin group, significant risk reductions persisted for any diabetes-related end point (21%, P = .01), myocardial infarction (33%, P = .005), and death from any cause (27%, P = .002).

The long-term follow-up to the UKPDS, like the long-term follow-up to the DCCT, demonstrated metabolic memory: that is, despite an early loss of glycemic differences after completion of the trial, a continued reduction in microvascular risk and an emergent risk reduction for myocardial infarction and death from any cause were observed.

These long-term randomized prospective trials in patients with type 1 and type 2 diabetes clearly show that the glucose hypothesis is in fact correct: intensive glucose control lowers the risk of both microvascular and macrovascular complications of diabetes.

IS THERE DISCORDANCE BETWEEN OLDER AND MORE RECENT TRIALS?

If the results of these older landmark clinical trials are true, why did the more recent clinical trials fail to show cardiovascular benefit with stricter glycemic control, and in one trial² demonstrate the potential for harm? (ACCORD² found an increased death rate in patients who received intensive therapy, targeting a hemoglobin A_1c below 6.0%.)

The answer lies in the populations studied. ACCORD,² VADT,³ and ADVANCE⁴ were performed in older patients with prior cardiac events or with several risk factors for cardiovascular events. The study populations were picked to increase the number of cardiac events in a short time frame. Therefore, extrapolating the results of these studies to the younger population of patients with diabetes, most of whom have yet to develop macrovascular disease, is inappropriate.

The available evidence suggests that early aggressive management of diabetes reduces the risk of macrovascular disease, but that this benefit is delayed. In the UKPDS and DCCT trials, it took 10 to 17 years to show cardiac benefit in younger patients.

The results of ACCORD,² VADT,³ and ADVANCE⁴ are important when considered in the correct clinical context. Two of these trials did demonstrate some microvascular benefit as a result of better glycemic control in older patients, many of whom had longstanding diabetes. These studies suggest that, in patients who already have established cardiovascular disease or have several risk factors for cardiovascular events, a less-strict glycemic target may be warranted.

These trials should not be interpreted as saying that glycemic control is unimportant in older patients at higher risk. Rather, they suggest that an individualized approach to diabetes management, supported by the most recent American Diabetes Association guidelines,⁹ is more appropriate.

Physicians may reasonably suggest a stricter A_1c goal (ie, < 6.5%) in certain patients if it can be achieved without significant hypoglycemia. Stricter glycemic targets would seem appropriate in patients recently diagnosed with diabetes, those who have a long life expectancy, and those who have not yet developed significant cardiovascular disease.⁹

However, in patients who already have developed advanced microvascular and macrovascular complications, who have long-standing diabetes, who have a history of severe hypoglycemia (or hypoglycemia unawareness), or who have a limited life expectancy or numerous adverse comorbidities, a less strict glycemic target (hemoglobin A_1c < 8%) may be more appropriate.⁹

CARDIOVASCULAR RISK, HYPOGLYCEMIA, AND ATTAINING GLYCEMIC TARGETS

Metformin, in the absence of contraindications or intolerability, is generally the recommended first-line therapy to manage glycemia in patients with type 2 diabetes mellitus.^10,11 However, there are only limited data to direct clinicians as to which antidiabetic medication to use if further therapy is required to obtain glycemic control.

Much of the cardiovascular and mortality risk associated with aggressive diabetes management (ie, lower A_1c targets) is related to hypoglycemia. Thus, antidiabetic therapies that pose no risk or only a low risk of hypoglycemia should be chosen, particularly in older patients and in those with known cardiovascular disease. This may allow for better glycemic control without the risk of hypoglycemia and adverse cardiovascular outcomes.

However, in practice, clinicians continue to use a sulfonylurea as the second-line agent. Although sulfonylureas may appear to be a great option because of their low cost, they are associated with a higher risk of hypoglycemic episodes than other classes of diabetes drugs. We need to consider the frequency and cost of hypoglycemic episodes and the potential morbidity associated with them, because these episodes are a barrier to our efforts to achieve better glycemic control.

Budnitz et al¹² reported that from 2007 through 2009, in US adults age 65 and older, insulins were implicated in 13.9% of hospitalizations related to adverse drug events, and oral hypoglycemic agents (ie, insulin secretagogues) in 10.7%.

Quilliam et al¹³ reported that hypoglycemia resulted in a mean cost of $17,564 for an inpatient admission, $1,387 for an emergency department visit, and $394 for an outpatient visit. Thus, the cost savings associated with prescribing a sulfonylurea vs one of the newer oral antidiabetic agents that do not increase the risk of hypoglycemia (unless used concurrently with insulin or an insulin secretagogue) can quickly be eroded by severe hypoglycemic episodes requiring medical care.

Moreover, once patients start to experience hypoglycemic episodes, they are very reluctant, as are their physicians, to intensify therapy, even if it is indicated by their elevated A_1c.

There are now seven classes of oral antidiabetic therapies other than insulin secretagogues (ie, other than sulfonylureas and the meglitinides nateglinide and repaglinide), as well as a few noninsulin injectable therapies (glucagon-like peptide-1 agonists), that are not associated with hypoglycemia. We believe these agents should be tried before prescribing an agent that carries the risk of hypoglycemia (ie, sulfonylureas).

If agents that do not cause hypoglycemia are used, more-aggressive glycemic targets may be achieved safely. The ACCORD study,² which included patients at high cardiovascular risk and aimed at an aggressive glycemic target of 6%, may have yielded much different results had agents that carry a high risk of hypoglycemia been excluded.

Of importance, cardiovascular risk is also influenced by the common comorbidities seen in patients with diabetes, such as hypertension and hypercholesterolemia. Intensive, multifactorial interventions that address not only glycemic control but also blood pressure and lipids and that include low-dose aspirin therapy have been shown to lower the risk of death from cardiovascular causes and the risk of cardiovascular events.¹⁴ Likewise, smoking cessation is very important in reducing cardiovascular risk, especially in patients with diabetes.¹⁵

CLINICAL TRIALS IN CONTEXT

In conclusion, there is more to diabetes management than cardiovascular complications. Clearly, improved glycemic control decreases the risk of retinopathy, nephropathy, and neuropathy in patients with type 1 and type 2 diabetes. The DCCT and UKPDS extension studies further found that excellent glycemic control decreases rates of cardiac events.

The best way to treat diabetes may be different in otherwise healthy younger patients who have yet to develop significant complications than it is in older patients known to have cardiovascular disease or several risk factors for cardiovascular events. The available evidence suggests it would be reasonable to aim for stricter glycemic targets in the younger patients and less stringent targets in the older patients, particularly in those with long-standing diabetes who have already developed significant micro- and macrovascular complications.

We should interpret clinical trials within their narrow clinical context, emphasizing the actual population of patients included in the study, so as to avoid the inappropriate extrapolation of the results to all.