Reviews

Liver cancer is increasing in prevalence; from 2000 to 2010, the prevalence increased from 7.1 per 100,000 to 8.4 per 100,000 people.¹ This increase is due in part to an increase in chronic liver diseases such as hepatitis B and C and nonalcoholic steatohepatitis.² In addition, liver metastases, especially from colorectal cancer and breast cancer, are also on the rise worldwide. More than 60% of patients with colorectal cancer will have a liver metastasis at some point in the course of their disease.

However, only 10% to 15% of patients with hepatocellular carcinoma are candidates for surgical resection.^3,4 And for patients who are not surgical candidates, there are currently no accepted guidelines on treatment.⁵ Treatment of metastatic liver cancer has consisted mainly of systemic chemotherapy, but if standard treatments fail, other options need to be considered.

A number of minimally invasive treatments are available for primary and metastatic liver cancer.⁶ These treatments are for the most part palliative, but in rare instances they are curative. They can be divided into percutaneous imaging-guided therapy (eg, radiofrequency ablation, microwave ablation) and four catheter-based transarterial therapies:

• Bland embolization
• Chemoembolization
• Chemoembolization with drug-eluting microspheres
• Yttrium-90 radioembolization.

In this article, we focus only on the four catheter-based transarterial therapies, providing a brief description of each and a discussion of potential postprocedural complications and the key elements of postprocedural care.

The rationale for catheter-based transarterial therapy

Primary and metastatic liver malignancies depend mainly on the hepatic arterial blood supply for their survival and growth, whereas normal liver tissue is supplied mainly by the portal vein. Therapy applied through the hepatic arterial system is distributed directly to malignant tissue and spares healthy liver tissue. (Note: The leg is the route of access for all catheter-based transarterial therapies.)

BLAND EMBOLIZATION

In transarterial bland embolization, tiny spheres of a neutral (ie, bland) material are injected into the distal branches of the arteries that supply the tumor. These microemboli, 45 to 150 µm in diameter,⁷ permanently occlude the blood vessels.

Bland embolization carries a risk of pulmonary embolism if there is shunting between the pulmonary and hepatic circulation via the hepatic vein.^8,9 Fortunately, this serious complication is rare. Technetium-99m macroaggregated albumin (Tc-99m MAA) scanning is done before the procedure to assess the risk.

Posttreatment care and follow-up

Patients require follow-up with contrast-enhanced computed tomography (CT) 6 to 8 weeks after the procedure to evaluate tumor regression.

Further treatment

If follow-up CT shows that the lesion or lesions have not regressed or have increased in size, the embolization procedure can be repeated about 12 weeks after the initial treatment. The most likely cause of a poor response to therapy is failure to adequately identify all tumor-supplying vessels.¹⁰

CHEMOEMBOLIZATION

Transarterial chemoembolization targets the blood supply of the tumor with a combination of chemotherapeutic drugs and an embolizing agent. Standard chemotherapy agents used include doxorubicin, cisplatin, and mitomycin-C. A microcatheter is advanced into the vessel supplying the tumor, and the combination drug is injected as close to the tumor as possible.¹¹

Transarterial chemoembolization is the most commonly performed hepatic artery-directed therapy for liver cancer. It has been used to treat solitary tumors as well as multifocal disease. It allows for maximum embolization potential while preserving liver function.

Posttreatment care and follow-up

Postembolization syndrome, characterized by low-grade fever, mild leukocytosis, and pain, is common after transarterial chemoembolization. Therefore, the patient is usually admitted to the hospital overnight for monitoring and control of symptoms such as pain and nausea. Mild abdominal pain is common and should resolve within several days; severe abdominal pain should be evaluated, as chemical and ischemic cholecystitis have been reported. Severe abdominal pain also raises concern for possible tumor rupture or liver infarction.

At discharge after chemoembolization, patients are instructed to report high fever, jaundice, or abdominal swelling

At the time of discharge, patients should be instructed to contact their clinician if they experience high fever, jaundice, or abdominal swelling. Liver function testing is not recommended within 7 to 10 days of treatment, as the expected rise in aminotransferase levels could prompt an unnecessary workup. Barring additional complications, patients should be seen in the office 2 weeks after the procedure.¹²

Lesions should be followed by serial contrast-enhanced CT to determine response to therapy. The current recommendation for stable patients is CT every 3 months for 2 years, and then every 6 months until active disease recurs.¹³

Safety concerns

A rare but serious concern after this procedure is fulminant hepatic failure, which has a high death rate. It has been reported in fewer than 1% of patients. Less severe complications include liver failure and infection.¹³

Further treatment

Patients with multifocal disease may require further treatment, usually 4 to 6 weeks after the initial procedure. If a transjugular intrahepatic portosystemic shunt is already in place, the patient can undergo chemoembolization as long as liver function is preserved. However, these patients generally have a poorer prognosis.

CHEMOEMBOLIZATION WITH DRUG-ELUTING MICROSPHERES

In transarterial chemoembolization with drug-eluting microspheres, beads loaded with chemotherapeutic drugs provide controlled delivery, resulting in both ischemia of the tumor and slow release of chemotherapy.

Several types of beads are currently available, with different degrees of affinity for chemotherapy agents. An advantage of the beads is that they can be used in patients with tumors that show aggressive shunting or in tumors that have vascular invasion. The technique for delivering the beads is similar to that used in standard chemoembolization.¹⁴

Posttreatment care and follow-up

Postembolization syndrome is common. Treatment usually consists of hydration and control of pain and nausea. Follow-up includes serial CT to evaluate tumor response.

Safety concerns

Overall, this procedure is safe. A phase 1 and 2 trial¹⁵ showed adverse effects similar to those seen in chemoembolization. The most common adverse effect was a transient increase in liver enzymes. Serious complications such as tumor rupture, spontaneous bacterial peritonitis, and liver failure were rare.

YTTRIUM-90 RADIOEMBOLIZATION

In yttrium-90 radioembolization, radioactive microspheres are injected into the hepatic arterial supply. The procedure involves careful planning and is usually completed in stages.

The first stage involves angiography to map the hepatic vascular anatomy, as well as prophylactic embolization to protect against unintended delivery of the radioactive drug to vessels of the gastrointestinal tract (such as a branch of the hepatic artery that may supply the duodenum), causing tissue necrosis. Another reason for mapping is to look for any potential shunt between the tumor’s blood supply and the lung^16,17 and thus prevent pulmonary embolism from the embolization procedure. The gastric mucosa and the salivary glands are also studied, as isolated gastric mucosal uptake indicates gastrointestinal vascular shunting.

The mapping stage involves injecting radioactive particles of technetium-99m microaggregated albumin, which are close in size to the yttrium-90 particles used during the actual procedure. The dose injected is usually 4 to 5 mCi (much lower than the typical tumor-therapy dose of 100–120 Gy), and imaging is done with either planar or single-photon emission CT. The patient is usually admitted for overnight observation after angiography.

In the second stage, 1 or 2 weeks later, the patient undergoes injection of the radiopharmaceuticals into the hepatic artery supplying the tumor. If disease burden is high or there is bilobar disease, the treatment is repeated in another 6 to 8 weeks. After the procedure, the patient is admitted to the hospital for observation by an inpatient team.

Posttreatment care and follow-up

The major concern after yttrium-90 radioembolization is reflux of the microspheres through unrecognized gastrointestinal channels,¹⁸ particularly into the mucosa of the stomach and proximal duodenum, causing the formation of nonhealing ulcers, which can cause major morbidity and even death. Antiulcer medications can be started immediately after the procedure.

Postembolization syndrome is frequently seen, and the fever usually responds to acet­a­minophen. Nausea and vomiting can be managed conservatively.¹⁹

The patient returns for a follow-up visit within 4 to 6 weeks of the injection procedure, mainly for assessment of liver function. A transient increase in liver enzymes and tumor markers may be seen at this time. A massive increase in liver enzyme levels should be investigated further.

Safety concerns

The postprocedural radiation exposure from the patient is within the acceptable safety range; therefore, no special precautions are necessary. However, since resin spheres are excreted in the urine, precautions are needed for urine disposal during the first 24 hours.^20,21

Further treatments

If there is multifocal disease or a poor response to the initial treatment, a second session can be done 6 to 8 weeks after the first one. Before the second session, the liver tumor is imaged.²² For hepatocellular carcinoma, imaging may show shrinkage and necrosis of the tumor. For metastatic tumors, this imaging is important as it may show either failure or progression of disease.²³ For this reason, functional imaging such as positron-emission tomography is important as it may show the extrahepatic spread of tumor, thereby halting further treatment. A complete blood cell count may also be done at 30 days to look for radiation-related cytopenia. A scrupulous log of the radiation dose received by the patient should be maintained.

PUNCTURE-SITE COMPLICATIONS

Hematoma

Hematoma at the puncture site is the most common complication of arterial access, with an incidence of 5% to 23%. The main clinical findings are erythema and swelling at the puncture site, with a palpable hardening of the skin. Pain and decreased range of motion in the affected extremity can also occur.

Simple hematomas exhibit a stable size and hemoglobin count and are managed conservatively. Initial management involves marking the site and checking frequently for a change in size, as well as applying pressure. Strict bed rest is recommended, with the affected leg kept straight for 4 to 6 hours. The hemoglobin concentration and hematocrit should be monitored for acute blood loss. Simple hematomas usually resolve in 2 to 4 weeks.

Complicated hematoma is characterized by continuous blood loss and can be compounded by a coagulopathy coexistent with underlying liver disease. Severe blood loss can result in hypotension and tachycardia with an acute drop in the hemoglobin concentration.

Of note, a complicated hematoma can manifest superficially in the groin and may not change size over time, as most of the bleeding is intrapelvic.

Complicated hematomas require management by an interventional radiologist, including urgent noncontrast CT of the pelvis to evaluate for bleeding. In severe cases, embolization or stent graft placement by the interventional radiologist may be necessary. Open surgical evacuation is usually done only when compartment syndrome is a concern.^24–26

Pseudoaneurysm

Pseudoaneurysm occurs in 0.5% to 9% of patients who undergo arterial puncture. It primarily arises from difficulty with cannulation of the artery and from inadequate compression after removal of the vascular sheath.

The signs of pseudoaneurysm are similar to those of hematoma, but it presents with a palpable thrill or bruit on auscultation. Ultrasonography is used for diagnosis.

As with hematoma treatment, bed rest and close monitoring are important. Mild pseudoaneurysm usually responds to manual compression for 20 to 30 minutes. More severe cases may require surgical intervention or percutaneous thrombin injection under ultrasonographic guidance.^25,27

Infection

Infection of the puncture site is rare, with an incidence of about 1%. However, with the advent of closure devices such as Angio-Seal (St. Jude Medical), the incidence of infection has been on the rise, as these devices leave a tract from the skin to the vessel, providing a nidus for infection.^25,28

The hallmarks of infection are straightforward and include pain, swelling, erythema, fever, and leukocytosis, and treatment involves antibiotics.

Nerve damage

In rare cases, puncture or postprocedural compression can damage surrounding nerves. The incidence of nerve damage is less than 0.5%. Symptoms include numbness and tingling at the access site and limb weakness. Treatment involves symptomatic management and physical therapy. Nerve damage can also result from nerve sheath compression by a hematoma.^25,29

Arterial thrombosis

Arterial thrombosis can occur at the site of sheath entry, but this can be avoided by administering anticoagulation during the procedure. Classic symptoms include the “5 P’s”: pain, pallor, paresthesia, pulselessness, and paralysis. Treatment depends on the clot burden, with small clots potentially dissolving and larger clots requiring possible thrombolysis, embolectomy, or surgery.^25,30

SYSTEMIC CONSIDERATIONS

Postembolization syndrome

Postembolization syndrome is characterized by low-grade fever, mild leukocytosis, and pain. Although not a true complication of the procedure, it is an expected event in postprocedural care and should not be confused with systemic infection.

Symptoms of postembolization syndrome peak within 5 days and can last up to 10 days

The pathophysiology of postembolization syndrome is not completely understood, but it is believed to be a sequela of liver necrosis and resulting inflammatory reaction.³¹ The incidence has been reported to be as high as 90% to 95%, with 81% of patients reporting nausea, vomiting, malaise, and myalgias; 42% of patients experience low-grade fever.³² Higher doses of chemotherapy and inadvertent embolization of the gallbladder have been associated with a higher incidence of postembolization syndrome.³²

Symptoms typically peak within 5 days of the procedure and can last up to 10 days. If symptoms do not resolve during this time, infection should be ruled out. Blood cultures and aspirates from infarcted liver tissue remain sterile in postembolization syndrome, thus helping to rule out infection.³²

Treatment with corticosteroids, analgesics, antinausea drugs, and intravenous fluids have all been used individually or in combination, with varying success rates. Prophylactic anti­biotic treatment does not appear to play a role.³³

Tumor lysis syndrome

Tumor lysis syndrome—a complex of severe metabolic disturbances potentially resulting in nephropathy and kidney failure—is extremely rare, with only a handful of individual case reports. It can occur with any embolization technique. Hsieh et al³⁴ reported two cases arising 24 hours to 3 days after treatment. Hsieh et al,³⁴ Burney,³⁵ and Sakamoto et al³⁶ reported tumor lysis syndrome in patients with tumors larger than 5 cm, suggesting that these patients may be at higher risk.

Tumor lysis syndrome typically presents with oliguria and subsequently progresses to electrolyte abnormalities, defined by Cairo and Bishop³⁷ as a 25% increase or decrease in the serum concentration of two of the following within 7 days after tumor therapy: uric acid, potassium, calcium, or phosphate. Treatment involves correction of electrolyte disturbances, as well as aggressive rehydration and allopurinol for high uric acid levels.

Hypersensitivity to iodinated contrast

Contrast reactions range from immediate (within 1 hour) to delayed (from 1 hour to several days after administration). The most common symptoms of an immediate reaction are pruritus, flushing, angioedema, bronchospasm, wheezing, hypotension, and shock. Delayed reactions typically involve mild to moderate skin rash, mild angioedema, minor erythema multiforme, and, rarely, Stevens-Johnson syndrome.³⁸ Dermatology consultation should always be considered for delayed reactions, particularly for severe skin manifestations.

Immediate reactions should be treated with intravenous (IV) fluid support and bronchodilators, and in life-threatening situations, epinephrine. Treatment of delayed reaction is guided by the symptoms. If the reaction is mild (pruritus or rash), secure IV access, have oxygen on standby, begin IV fluids, and consider giving diphenhydramine 50 mg IV or by mouth. Hydrocortisone 200 mg IV can be substituted if the patient has a diphen-hydramine allergy. For severe reactions, epinephrine (1:1,000 intramuscularly or 1:10,000 IV) should be given immediately.³⁹

Ideally, high-risk patients (ie, those with known contrast allergies) should avoid contrast medium if possible. However, if contrast is necessary, premedication should be provided. The American College of Radiology recommends the following preprocedural regimen: prednisone 50 mg by mouth 13 hours, 7 hours, and 1 hour before contrast administration, then 50 mg of diphenhydramine (IV, intramuscular, or oral) 1 hour before the procedure. Methylprednisolone 32 mg by mouth 12 hours and 2 hours before the procedure is an alternative to prednisone; 200 mg of IV hydrocortisone can be used if the patient cannot take oral medication.^40–42

Hypersensitivity to embolizing agents

In chemoembolization procedures, ethiodized oil is used as both a contrast medium and an occluding agent. This lipiodol suspension is combined and injected with the chemotherapy drug. Hypersensitivity reactions have been reported, but the mechanism is not well understood.

One study⁴³ showed a 3.2% occurrence of hypersensitivity to lipiodol combined with cisplatin, a frequently used combination. The most common reaction was dyspnea and urticaria (observed in 57% of patients); bronchospasm, altered mental status, and pruritus were also observed in lower frequencies. Treatment involved corticosteroids and antihistamines; blood pressure support with vasopressors was used as needed.⁴³

Contrast-induced nephropathy

Contrast-induced nephropathy is defined as a 25% rise in serum creatinine from baseline after exposure to iodinated contrast agents. Patients particularly at risk include those with preexisting renal impairment, diabetes mellitus, or acute renal failure due to dehydration. Other risk factors include age, preexisting cardiovascular disease, and hepatic impairment.

Prophylactic strategies rely primarily on intravenous hydration before exposure. The use of N-acetylcysteine can also be considered, but its effectiveness is controversial and it is not routinely recommended in the United States.

Managing acute renal failure, whether new or due to chronic renal impairment, should first involve rehydration. In cases of a severe rise in creatinine or uremia, dialysis should be considered as well as a nephrology consultation.^44,45

Liver cancer is increasing in prevalence; from 2000 to 2010, the prevalence increased from 7.1 per 100,000 to 8.4 per 100,000 people.¹ This increase is due in part to an increase in chronic liver diseases such as hepatitis B and C and nonalcoholic steatohepatitis.² In addition, liver metastases, especially from colorectal cancer and breast cancer, are also on the rise worldwide. More than 60% of patients with colorectal cancer will have a liver metastasis at some point in the course of their disease.

However, only 10% to 15% of patients with hepatocellular carcinoma are candidates for surgical resection.^3,4 And for patients who are not surgical candidates, there are currently no accepted guidelines on treatment.⁵ Treatment of metastatic liver cancer has consisted mainly of systemic chemotherapy, but if standard treatments fail, other options need to be considered.

A number of minimally invasive treatments are available for primary and metastatic liver cancer.⁶ These treatments are for the most part palliative, but in rare instances they are curative. They can be divided into percutaneous imaging-guided therapy (eg, radiofrequency ablation, microwave ablation) and four catheter-based transarterial therapies:

• Bland embolization
• Chemoembolization
• Chemoembolization with drug-eluting microspheres
• Yttrium-90 radioembolization.

In this article, we focus only on the four catheter-based transarterial therapies, providing a brief description of each and a discussion of potential postprocedural complications and the key elements of postprocedural care.

The rationale for catheter-based transarterial therapy

Primary and metastatic liver malignancies depend mainly on the hepatic arterial blood supply for their survival and growth, whereas normal liver tissue is supplied mainly by the portal vein. Therapy applied through the hepatic arterial system is distributed directly to malignant tissue and spares healthy liver tissue. (Note: The leg is the route of access for all catheter-based transarterial therapies.)

BLAND EMBOLIZATION

In transarterial bland embolization, tiny spheres of a neutral (ie, bland) material are injected into the distal branches of the arteries that supply the tumor. These microemboli, 45 to 150 µm in diameter,⁷ permanently occlude the blood vessels.

Bland embolization carries a risk of pulmonary embolism if there is shunting between the pulmonary and hepatic circulation via the hepatic vein.^8,9 Fortunately, this serious complication is rare. Technetium-99m macroaggregated albumin (Tc-99m MAA) scanning is done before the procedure to assess the risk.

Posttreatment care and follow-up

Patients require follow-up with contrast-enhanced computed tomography (CT) 6 to 8 weeks after the procedure to evaluate tumor regression.

Further treatment

If follow-up CT shows that the lesion or lesions have not regressed or have increased in size, the embolization procedure can be repeated about 12 weeks after the initial treatment. The most likely cause of a poor response to therapy is failure to adequately identify all tumor-supplying vessels.¹⁰

CHEMOEMBOLIZATION

Transarterial chemoembolization targets the blood supply of the tumor with a combination of chemotherapeutic drugs and an embolizing agent. Standard chemotherapy agents used include doxorubicin, cisplatin, and mitomycin-C. A microcatheter is advanced into the vessel supplying the tumor, and the combination drug is injected as close to the tumor as possible.¹¹

Transarterial chemoembolization is the most commonly performed hepatic artery-directed therapy for liver cancer. It has been used to treat solitary tumors as well as multifocal disease. It allows for maximum embolization potential while preserving liver function.

Posttreatment care and follow-up

Postembolization syndrome, characterized by low-grade fever, mild leukocytosis, and pain, is common after transarterial chemoembolization. Therefore, the patient is usually admitted to the hospital overnight for monitoring and control of symptoms such as pain and nausea. Mild abdominal pain is common and should resolve within several days; severe abdominal pain should be evaluated, as chemical and ischemic cholecystitis have been reported. Severe abdominal pain also raises concern for possible tumor rupture or liver infarction.

At discharge after chemoembolization, patients are instructed to report high fever, jaundice, or abdominal swelling

At the time of discharge, patients should be instructed to contact their clinician if they experience high fever, jaundice, or abdominal swelling. Liver function testing is not recommended within 7 to 10 days of treatment, as the expected rise in aminotransferase levels could prompt an unnecessary workup. Barring additional complications, patients should be seen in the office 2 weeks after the procedure.¹²

Lesions should be followed by serial contrast-enhanced CT to determine response to therapy. The current recommendation for stable patients is CT every 3 months for 2 years, and then every 6 months until active disease recurs.¹³

Safety concerns

A rare but serious concern after this procedure is fulminant hepatic failure, which has a high death rate. It has been reported in fewer than 1% of patients. Less severe complications include liver failure and infection.¹³

Further treatment

Patients with multifocal disease may require further treatment, usually 4 to 6 weeks after the initial procedure. If a transjugular intrahepatic portosystemic shunt is already in place, the patient can undergo chemoembolization as long as liver function is preserved. However, these patients generally have a poorer prognosis.

CHEMOEMBOLIZATION WITH DRUG-ELUTING MICROSPHERES

In transarterial chemoembolization with drug-eluting microspheres, beads loaded with chemotherapeutic drugs provide controlled delivery, resulting in both ischemia of the tumor and slow release of chemotherapy.

Several types of beads are currently available, with different degrees of affinity for chemotherapy agents. An advantage of the beads is that they can be used in patients with tumors that show aggressive shunting or in tumors that have vascular invasion. The technique for delivering the beads is similar to that used in standard chemoembolization.¹⁴

Posttreatment care and follow-up

Postembolization syndrome is common. Treatment usually consists of hydration and control of pain and nausea. Follow-up includes serial CT to evaluate tumor response.

Safety concerns

Overall, this procedure is safe. A phase 1 and 2 trial¹⁵ showed adverse effects similar to those seen in chemoembolization. The most common adverse effect was a transient increase in liver enzymes. Serious complications such as tumor rupture, spontaneous bacterial peritonitis, and liver failure were rare.

YTTRIUM-90 RADIOEMBOLIZATION

In yttrium-90 radioembolization, radioactive microspheres are injected into the hepatic arterial supply. The procedure involves careful planning and is usually completed in stages.

The first stage involves angiography to map the hepatic vascular anatomy, as well as prophylactic embolization to protect against unintended delivery of the radioactive drug to vessels of the gastrointestinal tract (such as a branch of the hepatic artery that may supply the duodenum), causing tissue necrosis. Another reason for mapping is to look for any potential shunt between the tumor’s blood supply and the lung^16,17 and thus prevent pulmonary embolism from the embolization procedure. The gastric mucosa and the salivary glands are also studied, as isolated gastric mucosal uptake indicates gastrointestinal vascular shunting.

The mapping stage involves injecting radioactive particles of technetium-99m microaggregated albumin, which are close in size to the yttrium-90 particles used during the actual procedure. The dose injected is usually 4 to 5 mCi (much lower than the typical tumor-therapy dose of 100–120 Gy), and imaging is done with either planar or single-photon emission CT. The patient is usually admitted for overnight observation after angiography.

In the second stage, 1 or 2 weeks later, the patient undergoes injection of the radiopharmaceuticals into the hepatic artery supplying the tumor. If disease burden is high or there is bilobar disease, the treatment is repeated in another 6 to 8 weeks. After the procedure, the patient is admitted to the hospital for observation by an inpatient team.

Posttreatment care and follow-up

The major concern after yttrium-90 radioembolization is reflux of the microspheres through unrecognized gastrointestinal channels,¹⁸ particularly into the mucosa of the stomach and proximal duodenum, causing the formation of nonhealing ulcers, which can cause major morbidity and even death. Antiulcer medications can be started immediately after the procedure.

Postembolization syndrome is frequently seen, and the fever usually responds to acet­a­minophen. Nausea and vomiting can be managed conservatively.¹⁹

The patient returns for a follow-up visit within 4 to 6 weeks of the injection procedure, mainly for assessment of liver function. A transient increase in liver enzymes and tumor markers may be seen at this time. A massive increase in liver enzyme levels should be investigated further.

Safety concerns

The postprocedural radiation exposure from the patient is within the acceptable safety range; therefore, no special precautions are necessary. However, since resin spheres are excreted in the urine, precautions are needed for urine disposal during the first 24 hours.^20,21

Further treatments

If there is multifocal disease or a poor response to the initial treatment, a second session can be done 6 to 8 weeks after the first one. Before the second session, the liver tumor is imaged.²² For hepatocellular carcinoma, imaging may show shrinkage and necrosis of the tumor. For metastatic tumors, this imaging is important as it may show either failure or progression of disease.²³ For this reason, functional imaging such as positron-emission tomography is important as it may show the extrahepatic spread of tumor, thereby halting further treatment. A complete blood cell count may also be done at 30 days to look for radiation-related cytopenia. A scrupulous log of the radiation dose received by the patient should be maintained.

PUNCTURE-SITE COMPLICATIONS

Hematoma

Hematoma at the puncture site is the most common complication of arterial access, with an incidence of 5% to 23%. The main clinical findings are erythema and swelling at the puncture site, with a palpable hardening of the skin. Pain and decreased range of motion in the affected extremity can also occur.

Simple hematomas exhibit a stable size and hemoglobin count and are managed conservatively. Initial management involves marking the site and checking frequently for a change in size, as well as applying pressure. Strict bed rest is recommended, with the affected leg kept straight for 4 to 6 hours. The hemoglobin concentration and hematocrit should be monitored for acute blood loss. Simple hematomas usually resolve in 2 to 4 weeks.

Complicated hematoma is characterized by continuous blood loss and can be compounded by a coagulopathy coexistent with underlying liver disease. Severe blood loss can result in hypotension and tachycardia with an acute drop in the hemoglobin concentration.

Of note, a complicated hematoma can manifest superficially in the groin and may not change size over time, as most of the bleeding is intrapelvic.

Complicated hematomas require management by an interventional radiologist, including urgent noncontrast CT of the pelvis to evaluate for bleeding. In severe cases, embolization or stent graft placement by the interventional radiologist may be necessary. Open surgical evacuation is usually done only when compartment syndrome is a concern.^24–26

Pseudoaneurysm

Pseudoaneurysm occurs in 0.5% to 9% of patients who undergo arterial puncture. It primarily arises from difficulty with cannulation of the artery and from inadequate compression after removal of the vascular sheath.

The signs of pseudoaneurysm are similar to those of hematoma, but it presents with a palpable thrill or bruit on auscultation. Ultrasonography is used for diagnosis.

As with hematoma treatment, bed rest and close monitoring are important. Mild pseudoaneurysm usually responds to manual compression for 20 to 30 minutes. More severe cases may require surgical intervention or percutaneous thrombin injection under ultrasonographic guidance.^25,27

Infection

Infection of the puncture site is rare, with an incidence of about 1%. However, with the advent of closure devices such as Angio-Seal (St. Jude Medical), the incidence of infection has been on the rise, as these devices leave a tract from the skin to the vessel, providing a nidus for infection.^25,28

The hallmarks of infection are straightforward and include pain, swelling, erythema, fever, and leukocytosis, and treatment involves antibiotics.

Nerve damage

In rare cases, puncture or postprocedural compression can damage surrounding nerves. The incidence of nerve damage is less than 0.5%. Symptoms include numbness and tingling at the access site and limb weakness. Treatment involves symptomatic management and physical therapy. Nerve damage can also result from nerve sheath compression by a hematoma.^25,29

Arterial thrombosis

Arterial thrombosis can occur at the site of sheath entry, but this can be avoided by administering anticoagulation during the procedure. Classic symptoms include the “5 P’s”: pain, pallor, paresthesia, pulselessness, and paralysis. Treatment depends on the clot burden, with small clots potentially dissolving and larger clots requiring possible thrombolysis, embolectomy, or surgery.^25,30

SYSTEMIC CONSIDERATIONS

Postembolization syndrome

Postembolization syndrome is characterized by low-grade fever, mild leukocytosis, and pain. Although not a true complication of the procedure, it is an expected event in postprocedural care and should not be confused with systemic infection.

Symptoms of postembolization syndrome peak within 5 days and can last up to 10 days

The pathophysiology of postembolization syndrome is not completely understood, but it is believed to be a sequela of liver necrosis and resulting inflammatory reaction.³¹ The incidence has been reported to be as high as 90% to 95%, with 81% of patients reporting nausea, vomiting, malaise, and myalgias; 42% of patients experience low-grade fever.³² Higher doses of chemotherapy and inadvertent embolization of the gallbladder have been associated with a higher incidence of postembolization syndrome.³²

Symptoms typically peak within 5 days of the procedure and can last up to 10 days. If symptoms do not resolve during this time, infection should be ruled out. Blood cultures and aspirates from infarcted liver tissue remain sterile in postembolization syndrome, thus helping to rule out infection.³²

Treatment with corticosteroids, analgesics, antinausea drugs, and intravenous fluids have all been used individually or in combination, with varying success rates. Prophylactic anti­biotic treatment does not appear to play a role.³³

Tumor lysis syndrome

Tumor lysis syndrome—a complex of severe metabolic disturbances potentially resulting in nephropathy and kidney failure—is extremely rare, with only a handful of individual case reports. It can occur with any embolization technique. Hsieh et al³⁴ reported two cases arising 24 hours to 3 days after treatment. Hsieh et al,³⁴ Burney,³⁵ and Sakamoto et al³⁶ reported tumor lysis syndrome in patients with tumors larger than 5 cm, suggesting that these patients may be at higher risk.

Tumor lysis syndrome typically presents with oliguria and subsequently progresses to electrolyte abnormalities, defined by Cairo and Bishop³⁷ as a 25% increase or decrease in the serum concentration of two of the following within 7 days after tumor therapy: uric acid, potassium, calcium, or phosphate. Treatment involves correction of electrolyte disturbances, as well as aggressive rehydration and allopurinol for high uric acid levels.

Hypersensitivity to iodinated contrast

Contrast reactions range from immediate (within 1 hour) to delayed (from 1 hour to several days after administration). The most common symptoms of an immediate reaction are pruritus, flushing, angioedema, bronchospasm, wheezing, hypotension, and shock. Delayed reactions typically involve mild to moderate skin rash, mild angioedema, minor erythema multiforme, and, rarely, Stevens-Johnson syndrome.³⁸ Dermatology consultation should always be considered for delayed reactions, particularly for severe skin manifestations.

Immediate reactions should be treated with intravenous (IV) fluid support and bronchodilators, and in life-threatening situations, epinephrine. Treatment of delayed reaction is guided by the symptoms. If the reaction is mild (pruritus or rash), secure IV access, have oxygen on standby, begin IV fluids, and consider giving diphenhydramine 50 mg IV or by mouth. Hydrocortisone 200 mg IV can be substituted if the patient has a diphen-hydramine allergy. For severe reactions, epinephrine (1:1,000 intramuscularly or 1:10,000 IV) should be given immediately.³⁹

Ideally, high-risk patients (ie, those with known contrast allergies) should avoid contrast medium if possible. However, if contrast is necessary, premedication should be provided. The American College of Radiology recommends the following preprocedural regimen: prednisone 50 mg by mouth 13 hours, 7 hours, and 1 hour before contrast administration, then 50 mg of diphenhydramine (IV, intramuscular, or oral) 1 hour before the procedure. Methylprednisolone 32 mg by mouth 12 hours and 2 hours before the procedure is an alternative to prednisone; 200 mg of IV hydrocortisone can be used if the patient cannot take oral medication.^40–42

Hypersensitivity to embolizing agents

In chemoembolization procedures, ethiodized oil is used as both a contrast medium and an occluding agent. This lipiodol suspension is combined and injected with the chemotherapy drug. Hypersensitivity reactions have been reported, but the mechanism is not well understood.

One study⁴³ showed a 3.2% occurrence of hypersensitivity to lipiodol combined with cisplatin, a frequently used combination. The most common reaction was dyspnea and urticaria (observed in 57% of patients); bronchospasm, altered mental status, and pruritus were also observed in lower frequencies. Treatment involved corticosteroids and antihistamines; blood pressure support with vasopressors was used as needed.⁴³

Contrast-induced nephropathy

Contrast-induced nephropathy is defined as a 25% rise in serum creatinine from baseline after exposure to iodinated contrast agents. Patients particularly at risk include those with preexisting renal impairment, diabetes mellitus, or acute renal failure due to dehydration. Other risk factors include age, preexisting cardiovascular disease, and hepatic impairment.

Prophylactic strategies rely primarily on intravenous hydration before exposure. The use of N-acetylcysteine can also be considered, but its effectiveness is controversial and it is not routinely recommended in the United States.

Managing acute renal failure, whether new or due to chronic renal impairment, should first involve rehydration. In cases of a severe rise in creatinine or uremia, dialysis should be considered as well as a nephrology consultation.^44,45

Liver cancer is increasing in prevalence; from 2000 to 2010, the prevalence increased from 7.1 per 100,000 to 8.4 per 100,000 people.¹ This increase is due in part to an increase in chronic liver diseases such as hepatitis B and C and nonalcoholic steatohepatitis.² In addition, liver metastases, especially from colorectal cancer and breast cancer, are also on the rise worldwide. More than 60% of patients with colorectal cancer will have a liver metastasis at some point in the course of their disease.

However, only 10% to 15% of patients with hepatocellular carcinoma are candidates for surgical resection.^3,4 And for patients who are not surgical candidates, there are currently no accepted guidelines on treatment.⁵ Treatment of metastatic liver cancer has consisted mainly of systemic chemotherapy, but if standard treatments fail, other options need to be considered.

A number of minimally invasive treatments are available for primary and metastatic liver cancer.⁶ These treatments are for the most part palliative, but in rare instances they are curative. They can be divided into percutaneous imaging-guided therapy (eg, radiofrequency ablation, microwave ablation) and four catheter-based transarterial therapies:

• Bland embolization
• Chemoembolization
• Chemoembolization with drug-eluting microspheres
• Yttrium-90 radioembolization.

In this article, we focus only on the four catheter-based transarterial therapies, providing a brief description of each and a discussion of potential postprocedural complications and the key elements of postprocedural care.

The rationale for catheter-based transarterial therapy

Primary and metastatic liver malignancies depend mainly on the hepatic arterial blood supply for their survival and growth, whereas normal liver tissue is supplied mainly by the portal vein. Therapy applied through the hepatic arterial system is distributed directly to malignant tissue and spares healthy liver tissue. (Note: The leg is the route of access for all catheter-based transarterial therapies.)

BLAND EMBOLIZATION

In transarterial bland embolization, tiny spheres of a neutral (ie, bland) material are injected into the distal branches of the arteries that supply the tumor. These microemboli, 45 to 150 µm in diameter,⁷ permanently occlude the blood vessels.

Bland embolization carries a risk of pulmonary embolism if there is shunting between the pulmonary and hepatic circulation via the hepatic vein.^8,9 Fortunately, this serious complication is rare. Technetium-99m macroaggregated albumin (Tc-99m MAA) scanning is done before the procedure to assess the risk.

Posttreatment care and follow-up

Patients require follow-up with contrast-enhanced computed tomography (CT) 6 to 8 weeks after the procedure to evaluate tumor regression.

Further treatment

If follow-up CT shows that the lesion or lesions have not regressed or have increased in size, the embolization procedure can be repeated about 12 weeks after the initial treatment. The most likely cause of a poor response to therapy is failure to adequately identify all tumor-supplying vessels.¹⁰

CHEMOEMBOLIZATION

Transarterial chemoembolization targets the blood supply of the tumor with a combination of chemotherapeutic drugs and an embolizing agent. Standard chemotherapy agents used include doxorubicin, cisplatin, and mitomycin-C. A microcatheter is advanced into the vessel supplying the tumor, and the combination drug is injected as close to the tumor as possible.¹¹

Transarterial chemoembolization is the most commonly performed hepatic artery-directed therapy for liver cancer. It has been used to treat solitary tumors as well as multifocal disease. It allows for maximum embolization potential while preserving liver function.

Posttreatment care and follow-up

Postembolization syndrome, characterized by low-grade fever, mild leukocytosis, and pain, is common after transarterial chemoembolization. Therefore, the patient is usually admitted to the hospital overnight for monitoring and control of symptoms such as pain and nausea. Mild abdominal pain is common and should resolve within several days; severe abdominal pain should be evaluated, as chemical and ischemic cholecystitis have been reported. Severe abdominal pain also raises concern for possible tumor rupture or liver infarction.

At discharge after chemoembolization, patients are instructed to report high fever, jaundice, or abdominal swelling

At the time of discharge, patients should be instructed to contact their clinician if they experience high fever, jaundice, or abdominal swelling. Liver function testing is not recommended within 7 to 10 days of treatment, as the expected rise in aminotransferase levels could prompt an unnecessary workup. Barring additional complications, patients should be seen in the office 2 weeks after the procedure.¹²

Lesions should be followed by serial contrast-enhanced CT to determine response to therapy. The current recommendation for stable patients is CT every 3 months for 2 years, and then every 6 months until active disease recurs.¹³

Safety concerns

A rare but serious concern after this procedure is fulminant hepatic failure, which has a high death rate. It has been reported in fewer than 1% of patients. Less severe complications include liver failure and infection.¹³

Further treatment

Patients with multifocal disease may require further treatment, usually 4 to 6 weeks after the initial procedure. If a transjugular intrahepatic portosystemic shunt is already in place, the patient can undergo chemoembolization as long as liver function is preserved. However, these patients generally have a poorer prognosis.

CHEMOEMBOLIZATION WITH DRUG-ELUTING MICROSPHERES

In transarterial chemoembolization with drug-eluting microspheres, beads loaded with chemotherapeutic drugs provide controlled delivery, resulting in both ischemia of the tumor and slow release of chemotherapy.

Several types of beads are currently available, with different degrees of affinity for chemotherapy agents. An advantage of the beads is that they can be used in patients with tumors that show aggressive shunting or in tumors that have vascular invasion. The technique for delivering the beads is similar to that used in standard chemoembolization.¹⁴

Posttreatment care and follow-up

Postembolization syndrome is common. Treatment usually consists of hydration and control of pain and nausea. Follow-up includes serial CT to evaluate tumor response.

Safety concerns

Overall, this procedure is safe. A phase 1 and 2 trial¹⁵ showed adverse effects similar to those seen in chemoembolization. The most common adverse effect was a transient increase in liver enzymes. Serious complications such as tumor rupture, spontaneous bacterial peritonitis, and liver failure were rare.

YTTRIUM-90 RADIOEMBOLIZATION

In yttrium-90 radioembolization, radioactive microspheres are injected into the hepatic arterial supply. The procedure involves careful planning and is usually completed in stages.

The first stage involves angiography to map the hepatic vascular anatomy, as well as prophylactic embolization to protect against unintended delivery of the radioactive drug to vessels of the gastrointestinal tract (such as a branch of the hepatic artery that may supply the duodenum), causing tissue necrosis. Another reason for mapping is to look for any potential shunt between the tumor’s blood supply and the lung^16,17 and thus prevent pulmonary embolism from the embolization procedure. The gastric mucosa and the salivary glands are also studied, as isolated gastric mucosal uptake indicates gastrointestinal vascular shunting.

The mapping stage involves injecting radioactive particles of technetium-99m microaggregated albumin, which are close in size to the yttrium-90 particles used during the actual procedure. The dose injected is usually 4 to 5 mCi (much lower than the typical tumor-therapy dose of 100–120 Gy), and imaging is done with either planar or single-photon emission CT. The patient is usually admitted for overnight observation after angiography.

In the second stage, 1 or 2 weeks later, the patient undergoes injection of the radiopharmaceuticals into the hepatic artery supplying the tumor. If disease burden is high or there is bilobar disease, the treatment is repeated in another 6 to 8 weeks. After the procedure, the patient is admitted to the hospital for observation by an inpatient team.

Posttreatment care and follow-up

The major concern after yttrium-90 radioembolization is reflux of the microspheres through unrecognized gastrointestinal channels,¹⁸ particularly into the mucosa of the stomach and proximal duodenum, causing the formation of nonhealing ulcers, which can cause major morbidity and even death. Antiulcer medications can be started immediately after the procedure.

Postembolization syndrome is frequently seen, and the fever usually responds to acet­a­minophen. Nausea and vomiting can be managed conservatively.¹⁹

The patient returns for a follow-up visit within 4 to 6 weeks of the injection procedure, mainly for assessment of liver function. A transient increase in liver enzymes and tumor markers may be seen at this time. A massive increase in liver enzyme levels should be investigated further.

Safety concerns

The postprocedural radiation exposure from the patient is within the acceptable safety range; therefore, no special precautions are necessary. However, since resin spheres are excreted in the urine, precautions are needed for urine disposal during the first 24 hours.^20,21

Further treatments

If there is multifocal disease or a poor response to the initial treatment, a second session can be done 6 to 8 weeks after the first one. Before the second session, the liver tumor is imaged.²² For hepatocellular carcinoma, imaging may show shrinkage and necrosis of the tumor. For metastatic tumors, this imaging is important as it may show either failure or progression of disease.²³ For this reason, functional imaging such as positron-emission tomography is important as it may show the extrahepatic spread of tumor, thereby halting further treatment. A complete blood cell count may also be done at 30 days to look for radiation-related cytopenia. A scrupulous log of the radiation dose received by the patient should be maintained.

PUNCTURE-SITE COMPLICATIONS

Hematoma

Hematoma at the puncture site is the most common complication of arterial access, with an incidence of 5% to 23%. The main clinical findings are erythema and swelling at the puncture site, with a palpable hardening of the skin. Pain and decreased range of motion in the affected extremity can also occur.

Simple hematomas exhibit a stable size and hemoglobin count and are managed conservatively. Initial management involves marking the site and checking frequently for a change in size, as well as applying pressure. Strict bed rest is recommended, with the affected leg kept straight for 4 to 6 hours. The hemoglobin concentration and hematocrit should be monitored for acute blood loss. Simple hematomas usually resolve in 2 to 4 weeks.

Complicated hematoma is characterized by continuous blood loss and can be compounded by a coagulopathy coexistent with underlying liver disease. Severe blood loss can result in hypotension and tachycardia with an acute drop in the hemoglobin concentration.

Of note, a complicated hematoma can manifest superficially in the groin and may not change size over time, as most of the bleeding is intrapelvic.

Complicated hematomas require management by an interventional radiologist, including urgent noncontrast CT of the pelvis to evaluate for bleeding. In severe cases, embolization or stent graft placement by the interventional radiologist may be necessary. Open surgical evacuation is usually done only when compartment syndrome is a concern.^24–26

Pseudoaneurysm

Pseudoaneurysm occurs in 0.5% to 9% of patients who undergo arterial puncture. It primarily arises from difficulty with cannulation of the artery and from inadequate compression after removal of the vascular sheath.

The signs of pseudoaneurysm are similar to those of hematoma, but it presents with a palpable thrill or bruit on auscultation. Ultrasonography is used for diagnosis.

As with hematoma treatment, bed rest and close monitoring are important. Mild pseudoaneurysm usually responds to manual compression for 20 to 30 minutes. More severe cases may require surgical intervention or percutaneous thrombin injection under ultrasonographic guidance.^25,27

Infection

Infection of the puncture site is rare, with an incidence of about 1%. However, with the advent of closure devices such as Angio-Seal (St. Jude Medical), the incidence of infection has been on the rise, as these devices leave a tract from the skin to the vessel, providing a nidus for infection.^25,28

The hallmarks of infection are straightforward and include pain, swelling, erythema, fever, and leukocytosis, and treatment involves antibiotics.

Nerve damage

In rare cases, puncture or postprocedural compression can damage surrounding nerves. The incidence of nerve damage is less than 0.5%. Symptoms include numbness and tingling at the access site and limb weakness. Treatment involves symptomatic management and physical therapy. Nerve damage can also result from nerve sheath compression by a hematoma.^25,29

Arterial thrombosis

Arterial thrombosis can occur at the site of sheath entry, but this can be avoided by administering anticoagulation during the procedure. Classic symptoms include the “5 P’s”: pain, pallor, paresthesia, pulselessness, and paralysis. Treatment depends on the clot burden, with small clots potentially dissolving and larger clots requiring possible thrombolysis, embolectomy, or surgery.^25,30

SYSTEMIC CONSIDERATIONS

Postembolization syndrome

Postembolization syndrome is characterized by low-grade fever, mild leukocytosis, and pain. Although not a true complication of the procedure, it is an expected event in postprocedural care and should not be confused with systemic infection.

Symptoms of postembolization syndrome peak within 5 days and can last up to 10 days

The pathophysiology of postembolization syndrome is not completely understood, but it is believed to be a sequela of liver necrosis and resulting inflammatory reaction.³¹ The incidence has been reported to be as high as 90% to 95%, with 81% of patients reporting nausea, vomiting, malaise, and myalgias; 42% of patients experience low-grade fever.³² Higher doses of chemotherapy and inadvertent embolization of the gallbladder have been associated with a higher incidence of postembolization syndrome.³²

Symptoms typically peak within 5 days of the procedure and can last up to 10 days. If symptoms do not resolve during this time, infection should be ruled out. Blood cultures and aspirates from infarcted liver tissue remain sterile in postembolization syndrome, thus helping to rule out infection.³²

Treatment with corticosteroids, analgesics, antinausea drugs, and intravenous fluids have all been used individually or in combination, with varying success rates. Prophylactic anti­biotic treatment does not appear to play a role.³³

Tumor lysis syndrome

Tumor lysis syndrome—a complex of severe metabolic disturbances potentially resulting in nephropathy and kidney failure—is extremely rare, with only a handful of individual case reports. It can occur with any embolization technique. Hsieh et al³⁴ reported two cases arising 24 hours to 3 days after treatment. Hsieh et al,³⁴ Burney,³⁵ and Sakamoto et al³⁶ reported tumor lysis syndrome in patients with tumors larger than 5 cm, suggesting that these patients may be at higher risk.

Tumor lysis syndrome typically presents with oliguria and subsequently progresses to electrolyte abnormalities, defined by Cairo and Bishop³⁷ as a 25% increase or decrease in the serum concentration of two of the following within 7 days after tumor therapy: uric acid, potassium, calcium, or phosphate. Treatment involves correction of electrolyte disturbances, as well as aggressive rehydration and allopurinol for high uric acid levels.

Hypersensitivity to iodinated contrast

Contrast reactions range from immediate (within 1 hour) to delayed (from 1 hour to several days after administration). The most common symptoms of an immediate reaction are pruritus, flushing, angioedema, bronchospasm, wheezing, hypotension, and shock. Delayed reactions typically involve mild to moderate skin rash, mild angioedema, minor erythema multiforme, and, rarely, Stevens-Johnson syndrome.³⁸ Dermatology consultation should always be considered for delayed reactions, particularly for severe skin manifestations.

Immediate reactions should be treated with intravenous (IV) fluid support and bronchodilators, and in life-threatening situations, epinephrine. Treatment of delayed reaction is guided by the symptoms. If the reaction is mild (pruritus or rash), secure IV access, have oxygen on standby, begin IV fluids, and consider giving diphenhydramine 50 mg IV or by mouth. Hydrocortisone 200 mg IV can be substituted if the patient has a diphen-hydramine allergy. For severe reactions, epinephrine (1:1,000 intramuscularly or 1:10,000 IV) should be given immediately.³⁹

Ideally, high-risk patients (ie, those with known contrast allergies) should avoid contrast medium if possible. However, if contrast is necessary, premedication should be provided. The American College of Radiology recommends the following preprocedural regimen: prednisone 50 mg by mouth 13 hours, 7 hours, and 1 hour before contrast administration, then 50 mg of diphenhydramine (IV, intramuscular, or oral) 1 hour before the procedure. Methylprednisolone 32 mg by mouth 12 hours and 2 hours before the procedure is an alternative to prednisone; 200 mg of IV hydrocortisone can be used if the patient cannot take oral medication.^40–42

Hypersensitivity to embolizing agents

In chemoembolization procedures, ethiodized oil is used as both a contrast medium and an occluding agent. This lipiodol suspension is combined and injected with the chemotherapy drug. Hypersensitivity reactions have been reported, but the mechanism is not well understood.

One study⁴³ showed a 3.2% occurrence of hypersensitivity to lipiodol combined with cisplatin, a frequently used combination. The most common reaction was dyspnea and urticaria (observed in 57% of patients); bronchospasm, altered mental status, and pruritus were also observed in lower frequencies. Treatment involved corticosteroids and antihistamines; blood pressure support with vasopressors was used as needed.⁴³

Contrast-induced nephropathy

Contrast-induced nephropathy is defined as a 25% rise in serum creatinine from baseline after exposure to iodinated contrast agents. Patients particularly at risk include those with preexisting renal impairment, diabetes mellitus, or acute renal failure due to dehydration. Other risk factors include age, preexisting cardiovascular disease, and hepatic impairment.

Prophylactic strategies rely primarily on intravenous hydration before exposure. The use of N-acetylcysteine can also be considered, but its effectiveness is controversial and it is not routinely recommended in the United States.

Managing acute renal failure, whether new or due to chronic renal impairment, should first involve rehydration. In cases of a severe rise in creatinine or uremia, dialysis should be considered as well as a nephrology consultation.^44,45

Carotid artery disease that is asymptomatic poses a dilemma: Should the patient undergo revascularization (surgical carotid endarterectomy or percutaneous stenting) or receive medical therapy alone?

On one hand, because one consequence of carotid atherosclerosis—ischemic stroke—can be devastating or deadly, many physicians and patients would rather “do something,” ie, proceed with surgery. Furthermore, several randomized trials^1–4 found carotid endarterectomy superior to medical therapy.

On the other hand, these trials were conducted in the 1990s. Surgery has improved since then, but so has medical therapy. And if we re-examine the data from the trials in terms of the absolute risk reduction and number needed to treat, as opposed to the relative risk reduction, surgery may appear less beneficial.

Needed is a way to identify patients who would benefit from surgery and those who would more likely be harmed. Research in that direction is ongoing.

Here, we present a simple algorithmic approach to managing asymptomatic carotid artery stenosis based on the patient’s age, sex, and life expectancy. Our approach is based on a review of the best available evidence.

UP TO 8% OF ADULTS HAVE STENOSIS

Stroke is the third largest cause of death in the United States and the leading cause of disability.⁵ From 10% to 15% of strokes are associated with carotid artery stenosis.^6,7

The prevalence of asymptomatic carotid disease, defined as stenosis greater than 50%, ranges from 4% to 8% in adults.⁸

However, major societies recommend against screening for carotid stenosis in the general population.^9–12 Similarly, the US Preventive Services Task Force also discourages the use of carotid auscultation as screening in the general population (Table 1).¹³ Generally, cases of asymptomatic carotid stenosis are diagnosed by ultrasonography after the patient’s physician happens to hear a bruit during a routine examination, during a preoperative assessment, or after the patient suffers a transient ischemic attack or stroke on the contralateral side.

CLASS II RECOMMENDATIONS FOR SURGERY OR STENTING

There are well-established guidelines for managing symptomatic carotid disease,¹⁴ based on evidence from the North American Symptomatic Carotid Endarterectomy Trial¹⁵ and the European Carotid Surgery Trial,¹⁶ both from 1998. But how to manage asymptomatic carotid disease remains uncertain.

If stenosis of the internal carotid artery is greater than 70% on ultrasonography, computed tomography, or magnetic resonance imaging, and if the risk of perioperative stroke and death is low (< 3%), current guidelines¹⁴ give carotid endarterectomy a class IIa recommendation (ie, evidence is conflicting, but the weight of evidence is in favor), and they give prophylactic carotid artery stenting with optimal medical treatment a class IIb recommendation (efficacy is less well established).⁵

But medical management has improved, and new data suggest that this improvement may override the minimal net benefit of intervention in some patients.¹⁷ Some authors suggest that it is best to use patient characteristics and imaging features to guide treatment.¹⁸

EVIDENCE TO SUPPORT CAROTID REVASCULARIZATION

Three major trials (Table 2) published nearly 20 years ago provide the foundation of the current guidelines:

• the Endarterectomy for Asymptomatic Carotid Atherosclerosis Study (ACAS)¹
• the Asymptomatic Carotid Surgery Trial (ACST)^2,3
• the Veterans Affairs (VA) Cooperative Study.⁴

A Cochrane review of these trials,¹⁹ where medical therapy consisted only of aspirin and little use of statin therapy, found that carotid endarterectomy reduced the rate of perioperative stroke or death or any subsequent stroke in the next 3 years by 31% (relative risk 69%, 95% confidence interval [CI] 0.57–0.83). “Perioperative” was defined as the period from randomization until 30 days after surgery in the surgical group and an equivalent period in the medical group.

Moreover, carotid endarterectomy reduced the rate of disabling or fatal nonperioperative stroke by 50% compared with medical management alone.^1,2,19 Patients who had contralateral symptomatic disease or who had undergone contralateral carotid endarterectomy seemed to benefit more from the procedure than those who had not.¹⁹

Also, the ACST investigators found that revascularization was associated with a reduction in contralateral strokes (which occurred in 39 vs 64 patients, P = .01) independent of contralateral symptoms or contralateral carotid endarterectomy.^2,3 The exact mechanism is unknown but could be related to better blood pressure control and risk factor modification after carotid endarterectomy.

Another factor supporting revascularization is that the outcomes of revascularization have improved over time. In 2010, the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)²⁰ reported a 30-day periprocedural incidence of death or stroke of only 1.4%, compared with 2.9% in the earlier landmark trials.

Stenting is a noninferior alternative

For patients who have asymptomatic stenosis greater than 80% on color duplex ultrasonography and a risk of stroke or death during carotid endarterectomy that is prohibitively high (> 3%), carotid stenting has proved to be a noninferior alternative.^21,22

The Stenting and Angioplasty With Protection of Patients With High Risk for Endarterectomy (SAPPHIRE) trial²¹ reported a risk of death, stroke, or myocardial infarction of about 5% at 30 days and 10% at 1 year after stenting. A recent observational study revealed lower perioperative complication rates, with a risk of death or stroke of about 3%, which satisfy current guideline requirements.²³

To be deemed at high surgical risk and therefore eligible for the SAPPHIRE trial,²¹ patients had to have clinically significant cardiac disease, severe pulmonary disease, contralateral carotid occlusion, contralateral laryngeal-nerve palsy, recurrent stenosis after carotid endarterectomy, previous radical neck surgery or radiation therapy to the neck, or age greater than 80.

EVIDENCE AGAINST CAROTID REVASCULARIZATION

Although carotid revascularization has evidence to support it, further interpretation of the data may lessen its apparent benefits.

Small absolute benefit, high number needed to treat

If we compare the relative risk reduction for the outcome of perioperative death or any stroke over 5 years (30% to 50%) vs the absolute risk reduction (4% to 5.9%), revascularization seems less attractive.¹⁹

Relative risk reduction in death or stroke with carotid surgery is 30%–50%; absolute risk reduction is 4%–5.9%

The benefit may be further diminished if we consider only strokes related to large vessels, since up to 45% of strokes in patients with carotid disease are lacunar or cardioembolic.²⁴ Assessing for prevention of large-vessel stroke using the ACAS data, the benefit of carotid endarterectomy for prevention of stroke is further decreased to a 3.5% absolute risk reduction, and the number needed to treat for 2 years increases from 62 to 111.^24,25 Nevertheless, revascularization is necessary in appropriately selected patients, as a cerebrovascular event can cause life-altering changes to a patient’s cognitive, emotional, and physical condition.²⁶

Medical therapy—and surgery—are evolving

The optimal medical management used in the landmark studies was significantly different from what is currently recommended. The ACAS trial¹⁸ used only aspirin as optimal medical management, with no mention of statins. In the ACST trial,^2,3 the use of statins increased over time, from 7% to 11% at the beginning of the trial to 80% to 82% at the end.

On the other hand, the ACAS¹ surgeons were required to have an excellent safety record to participate. This might have compromised the trial’s validity or our ability to generalize its conclusions.

Recent data from Abbott¹⁷ suggested a loss of a statistically significant surgical advantage in prevention of ipsilateral stroke and transient ischemic attack from the early 1990s. This is most likely explained by improved medical therapy, since there was a 22% increase in baseline proportion of patients receiving antiplatelet therapy from 1985 to 2007, with 60% of patients taking antihypertensive drugs and 30% of patients taking lipid-lowering drugs. Moreover, since 2001, the annual rates of ipsilateral stroke in patients receiving medical management alone fell below those of patients who underwent carotid endarterectomy in the ACAS trial.

The analysis by Abbott¹⁷ has major limitations: inclusion of small studies, many crossover patients, and heterogeneity. In support of this allegation, a small trial (33 patients) reported a risk of stroke ipsilateral to an asymptomatic carotid stenosis as low as 0.34% per year.²⁵ Even when contrasting the outcomes of medical therapy against those of current carotid endarterectomy, in which the rate of perioperative stroke and death have fallen to 0.88% to 1.7%,^17,27,28 there is concern that the risk associated with surgery may outweigh the long-term benefit.

Flaws in the landmark trials

Beyond the debate of the questionable benefit of revascularization, well-defined flaws in the landmark trials weaken or limit their influence on current treatment guidelines and protocols for deciding whether to revascularize.

No significant benefit was found for patients over age 75.^2,3 This was thought to be due to decreased life expectancy, since the benefit from revascularization becomes significant after 3 years from intervention.^1–3 Also, studies have shown that increasing age is associated with a higher risk of perioperative stroke and death.^20,21

Women showed no benefit at 5 years and only a trend toward benefit at 10 years (P = .05),² likely from a higher rate of periprocedural strokes.

Blacks and Hispanics were underrepresented in the landmark studies,¹⁹ while one observational study reported a higher incidence of in-hospital stroke after carotid endarterectomy in black patients (6.6%) than in white patients (2%).²⁹

When associated with contralateral carotid occlusion, carotid endarterectomy carries a higher risk of perioperative stroke or death.^23,30,31

Carotid revascularization failed to reduce the risk of death—the total number of deaths within 10 years was not significantly reduced by immediate carotid endarterectomy compared with deferring the procedure.²

EVIDENCE SUPPORTING OPTIMAL MEDICAL MANAGEMENT

Optimal medical therapy mainly consists of antiplatelet therapy, blood pressure management, diabetic glycemic control, and statin therapy along with lifestyle changes including smoking cessation, exercise, and weight loss (Table 3).⁹ Detailed recommendations are provided in the American Heart Association/American Stroke Association guidelines for primary prevention of stroke.³²

Antiplatelet therapy has been shown to reduce the incidence of stroke by 25%. There is no added benefit in combining antiplatelet agents unless the patient has concomitant symptomatic coronary artery disease, recent coronary stenting, or severe peripheral artery disease.^33,34

Blood pressure control can reduce the incidence of stroke by 30% to 40%, and recent data suggest that drugs working on the renin-angiotensin system offer more benefit than beta-blockers for the same reduction in blood pressure.^34,35

Diabetic glycemic control is supported, as higher hemoglobin A_1c and fasting glucose values are associated with higher relative risk of stroke.^32,36,37 However, the stroke rate does not differ significantly between patients receiving intensive therapy and those receiving standard therapy.³⁴

Statins actually shrink carotid plaques and reduce the risk of stroke by 15% for each 10% reduction in low-density lipoprotein cholesterol. It is estimated that statin therapy confers a 30% relative risk reduction of stroke over 20 years.^34,38–41

Smoking increases the overall risk of stroke by 150%, making its cessation mandatory.⁴²

HIGH-RISK FEATURES FOR STROKE IN ASYMPTOMATIC CAROTID STENOSIS

Studies have tried to identify risk factors for stroke, so that patients at high risk could undergo revascularization and benefit from it. However, no well-defined high-risk features have yet been described that would identify patients who would benefit from early surgery.

For instance, no correlation has been found between age, sex, diabetes mellitus, lipid levels, or smoking and progression of disease.⁴³ In contrast, having either contralateral symptomatic carotid disease or contralateral total occlusion translated into a higher ipsilateral stroke risk.¹⁸ And in several studies, the 5-year risk of ipsilateral stroke was as high as 16.2% for those with 60% to 99% stenosis.^1,2,18,24,43

Features of the plaque itself

More recently, there has been a focus on plaque evaluation to predict outcomes.

Statins shrink carotid plaques and reduce the risk of stroke by 15% for each 10% reduction in LDL-C

Percent stenosis. An increased risk of death or stroke has been reported with higher degrees of stenosis or plaque progression.^44,45 The gross annual risk of ipsilateral stroke increases from 1.5% with stenosis of 60% to 70%, to 4.2% with stenosis of 71% to 90%, and to 7% with stenosis of 91% to 99%. Nevertheless, current data are insufficient to determine whether there is increasing benefit from surgery with increasing degree of stenosis in asymptomatic carotid disease.^1,3,24,44

Plaque progression translates to a 7.2% absolute increase in the incidence of stroke (1.1% if the plaque is stable vs 8.3% if the plaque is progressing). Interestingly, plaque progression to greater than 80% stenosis results in worse outcomes (relative risk 3.4, 95% CI 1.5–7.8) compared with the same level of stenosis without recent progression.³³

Intimal wall thickening of more than 1.15 mm confers a hazard ratio for stroke of 3 (95% CI 1.48–6.11).⁴⁶

Increased echolucency also confers a hazard ratio for stroke of 3 (95% CI 1.4–8.0).⁴⁶

A low gray-scale median (a surrogate of plaque composition) and plaque area have been identified as independent predictors of ipsilateral events.⁴⁴

Embolic signals on transcranial Doppler ultrasonography (Figure 1) have been associated with a hazard ratio for stroke of 2.54 over 2 years.⁴⁷

Carotid plaques predominantly composed of lipid-rich necrotic cores carry a higher risk of stroke (hazard ratio 7.2, 95% CI 1.12–46.20).⁴⁸

High tensile stress (circumferential wall tension divided by the intima-media thickness), and fibrous cap thickening (< 500 µm) predict plaque rupture.⁴⁹

Plaque ulceration. The risk of stroke increases with worsening degree of plaque ulceration: 0.4% per year for type A ulcerated plaques (small minimal excavations) compared with 12.5% for type B (large obvious excavations) and type C (multiple cavities or cavernous).⁵⁰

Low cerebrovascular reactivity. Perfusion studies such as cerebrovascular reactivity evaluate changes in cerebral blood flow in response to a stimulus such as inhaled carbon dioxide, breath-holding, or acetazolamide. This may provide a useful index of cerebral vascular function. For instance, low reactivity has been associated with ipsilateral ischemic events (odds ratio 14.4, 95% CI 2.63–78.74, P = .0021).^51,52 Silvestrini et al⁵³ reported that the incidence of ipsilateral cerebrovascular ischemic events was 4.1% per year in patients who had normal cerebral vasoreactivity during breath-holding, vs 13.9% in those with low cerebral reactivity.

BEST MEDICAL THERAPY, ALONE OR COMBINED WITH REVASCULARIZATION

For carotid revascularization to be a viable option for asymptomatic carotid stenosis, the morbidity and mortality rates associated with the operation must be less than the incidence of neurologic events in patients who do not undergo the operation.⁵⁴ An important caveat is that the longer a patient survives after carotid endarterectomy, the greater the potential benefit, since the adverse consequences of surgery are generally limited to the perioperative period.¹⁹

The current evidence regarding medical management of asymptomatic carotid stenosis suggests that the rate of ipsilateral stroke is now lower than it was in the control groups in the landmark trials.^{2,3,17,45,47,55,56} Ultimately, adherence to current best medical management takes priority over the decision to revascularize. The best current medical therapy includes, but is not limited to, antithrombotic therapy, statin therapy, blood pressure control, diabetes management, smoking cessation, and lifestyle changes (Table 3).

As noted above, stroke risk seems variable in the asymptomatic population according to the presence or absence of risk factors. Yet no well-defined “high-risk stroke profile” has been identified. Therefore, a patient-by-patient decision based on best available evidence should identify patients who may benefit from carotid revascularization. If asymptomatic carotid stenosis of 70% to 99% is found, factors that favor revascularization are male sex, younger age, and longer life expectancy (Figure 2).

For those with intermediate or high-risk surgical features, uncertainty exists in management since no studies have compared revascularization against medical management only in this group of patients.¹ However, data from high-risk cohorts had high enough complication rates in both intervention arms to question the benefit of revascularization over medical therapy.^20,21 Therefore, the individual perioperative risk of stroke, myocardial infarction, and death must be weighed against the potential benefit of revascularization for each patient.

If revascularization is pursued, studies have demonstrated that carotid artery stenting is not inferior to endarterectomy^15,16 in high-surgical-risk patients. However, the revascularization approach must be tailored to the patient profile, since stenting demonstrated a lower risk of periprocedural myocardial infarction but a higher risk of stroke compared with endarteretomy.²⁰

Finally, the current acceptable risks of perioperative stroke and death must be revised if revascularization is elected. Current data suggest that a lower threshold—around 1.4%—can be used.²⁰ Moreover, further guidelines must determine the impact of adding myocardial infarction to the tolerable perioperative risks, since it has been excluded from main trials and guidelines.²⁰

Carotid artery disease that is asymptomatic poses a dilemma: Should the patient undergo revascularization (surgical carotid endarterectomy or percutaneous stenting) or receive medical therapy alone?

On one hand, because one consequence of carotid atherosclerosis—ischemic stroke—can be devastating or deadly, many physicians and patients would rather “do something,” ie, proceed with surgery. Furthermore, several randomized trials^1–4 found carotid endarterectomy superior to medical therapy.

On the other hand, these trials were conducted in the 1990s. Surgery has improved since then, but so has medical therapy. And if we re-examine the data from the trials in terms of the absolute risk reduction and number needed to treat, as opposed to the relative risk reduction, surgery may appear less beneficial.

Needed is a way to identify patients who would benefit from surgery and those who would more likely be harmed. Research in that direction is ongoing.

Here, we present a simple algorithmic approach to managing asymptomatic carotid artery stenosis based on the patient’s age, sex, and life expectancy. Our approach is based on a review of the best available evidence.

UP TO 8% OF ADULTS HAVE STENOSIS

Stroke is the third largest cause of death in the United States and the leading cause of disability.⁵ From 10% to 15% of strokes are associated with carotid artery stenosis.^6,7

The prevalence of asymptomatic carotid disease, defined as stenosis greater than 50%, ranges from 4% to 8% in adults.⁸

However, major societies recommend against screening for carotid stenosis in the general population.^9–12 Similarly, the US Preventive Services Task Force also discourages the use of carotid auscultation as screening in the general population (Table 1).¹³ Generally, cases of asymptomatic carotid stenosis are diagnosed by ultrasonography after the patient’s physician happens to hear a bruit during a routine examination, during a preoperative assessment, or after the patient suffers a transient ischemic attack or stroke on the contralateral side.

CLASS II RECOMMENDATIONS FOR SURGERY OR STENTING

There are well-established guidelines for managing symptomatic carotid disease,¹⁴ based on evidence from the North American Symptomatic Carotid Endarterectomy Trial¹⁵ and the European Carotid Surgery Trial,¹⁶ both from 1998. But how to manage asymptomatic carotid disease remains uncertain.

If stenosis of the internal carotid artery is greater than 70% on ultrasonography, computed tomography, or magnetic resonance imaging, and if the risk of perioperative stroke and death is low (< 3%), current guidelines¹⁴ give carotid endarterectomy a class IIa recommendation (ie, evidence is conflicting, but the weight of evidence is in favor), and they give prophylactic carotid artery stenting with optimal medical treatment a class IIb recommendation (efficacy is less well established).⁵

But medical management has improved, and new data suggest that this improvement may override the minimal net benefit of intervention in some patients.¹⁷ Some authors suggest that it is best to use patient characteristics and imaging features to guide treatment.¹⁸

EVIDENCE TO SUPPORT CAROTID REVASCULARIZATION

Three major trials (Table 2) published nearly 20 years ago provide the foundation of the current guidelines:

• the Endarterectomy for Asymptomatic Carotid Atherosclerosis Study (ACAS)¹
• the Asymptomatic Carotid Surgery Trial (ACST)^2,3
• the Veterans Affairs (VA) Cooperative Study.⁴

A Cochrane review of these trials,¹⁹ where medical therapy consisted only of aspirin and little use of statin therapy, found that carotid endarterectomy reduced the rate of perioperative stroke or death or any subsequent stroke in the next 3 years by 31% (relative risk 69%, 95% confidence interval [CI] 0.57–0.83). “Perioperative” was defined as the period from randomization until 30 days after surgery in the surgical group and an equivalent period in the medical group.

Moreover, carotid endarterectomy reduced the rate of disabling or fatal nonperioperative stroke by 50% compared with medical management alone.^1,2,19 Patients who had contralateral symptomatic disease or who had undergone contralateral carotid endarterectomy seemed to benefit more from the procedure than those who had not.¹⁹

Also, the ACST investigators found that revascularization was associated with a reduction in contralateral strokes (which occurred in 39 vs 64 patients, P = .01) independent of contralateral symptoms or contralateral carotid endarterectomy.^2,3 The exact mechanism is unknown but could be related to better blood pressure control and risk factor modification after carotid endarterectomy.

Another factor supporting revascularization is that the outcomes of revascularization have improved over time. In 2010, the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)²⁰ reported a 30-day periprocedural incidence of death or stroke of only 1.4%, compared with 2.9% in the earlier landmark trials.

Stenting is a noninferior alternative

For patients who have asymptomatic stenosis greater than 80% on color duplex ultrasonography and a risk of stroke or death during carotid endarterectomy that is prohibitively high (> 3%), carotid stenting has proved to be a noninferior alternative.^21,22

The Stenting and Angioplasty With Protection of Patients With High Risk for Endarterectomy (SAPPHIRE) trial²¹ reported a risk of death, stroke, or myocardial infarction of about 5% at 30 days and 10% at 1 year after stenting. A recent observational study revealed lower perioperative complication rates, with a risk of death or stroke of about 3%, which satisfy current guideline requirements.²³

To be deemed at high surgical risk and therefore eligible for the SAPPHIRE trial,²¹ patients had to have clinically significant cardiac disease, severe pulmonary disease, contralateral carotid occlusion, contralateral laryngeal-nerve palsy, recurrent stenosis after carotid endarterectomy, previous radical neck surgery or radiation therapy to the neck, or age greater than 80.

EVIDENCE AGAINST CAROTID REVASCULARIZATION

Although carotid revascularization has evidence to support it, further interpretation of the data may lessen its apparent benefits.

Small absolute benefit, high number needed to treat

If we compare the relative risk reduction for the outcome of perioperative death or any stroke over 5 years (30% to 50%) vs the absolute risk reduction (4% to 5.9%), revascularization seems less attractive.¹⁹

Relative risk reduction in death or stroke with carotid surgery is 30%–50%; absolute risk reduction is 4%–5.9%

The benefit may be further diminished if we consider only strokes related to large vessels, since up to 45% of strokes in patients with carotid disease are lacunar or cardioembolic.²⁴ Assessing for prevention of large-vessel stroke using the ACAS data, the benefit of carotid endarterectomy for prevention of stroke is further decreased to a 3.5% absolute risk reduction, and the number needed to treat for 2 years increases from 62 to 111.^24,25 Nevertheless, revascularization is necessary in appropriately selected patients, as a cerebrovascular event can cause life-altering changes to a patient’s cognitive, emotional, and physical condition.²⁶

Medical therapy—and surgery—are evolving

The optimal medical management used in the landmark studies was significantly different from what is currently recommended. The ACAS trial¹⁸ used only aspirin as optimal medical management, with no mention of statins. In the ACST trial,^2,3 the use of statins increased over time, from 7% to 11% at the beginning of the trial to 80% to 82% at the end.

On the other hand, the ACAS¹ surgeons were required to have an excellent safety record to participate. This might have compromised the trial’s validity or our ability to generalize its conclusions.

Recent data from Abbott¹⁷ suggested a loss of a statistically significant surgical advantage in prevention of ipsilateral stroke and transient ischemic attack from the early 1990s. This is most likely explained by improved medical therapy, since there was a 22% increase in baseline proportion of patients receiving antiplatelet therapy from 1985 to 2007, with 60% of patients taking antihypertensive drugs and 30% of patients taking lipid-lowering drugs. Moreover, since 2001, the annual rates of ipsilateral stroke in patients receiving medical management alone fell below those of patients who underwent carotid endarterectomy in the ACAS trial.

The analysis by Abbott¹⁷ has major limitations: inclusion of small studies, many crossover patients, and heterogeneity. In support of this allegation, a small trial (33 patients) reported a risk of stroke ipsilateral to an asymptomatic carotid stenosis as low as 0.34% per year.²⁵ Even when contrasting the outcomes of medical therapy against those of current carotid endarterectomy, in which the rate of perioperative stroke and death have fallen to 0.88% to 1.7%,^17,27,28 there is concern that the risk associated with surgery may outweigh the long-term benefit.

Flaws in the landmark trials

Beyond the debate of the questionable benefit of revascularization, well-defined flaws in the landmark trials weaken or limit their influence on current treatment guidelines and protocols for deciding whether to revascularize.

No significant benefit was found for patients over age 75.^2,3 This was thought to be due to decreased life expectancy, since the benefit from revascularization becomes significant after 3 years from intervention.^1–3 Also, studies have shown that increasing age is associated with a higher risk of perioperative stroke and death.^20,21

Women showed no benefit at 5 years and only a trend toward benefit at 10 years (P = .05),² likely from a higher rate of periprocedural strokes.

Blacks and Hispanics were underrepresented in the landmark studies,¹⁹ while one observational study reported a higher incidence of in-hospital stroke after carotid endarterectomy in black patients (6.6%) than in white patients (2%).²⁹

When associated with contralateral carotid occlusion, carotid endarterectomy carries a higher risk of perioperative stroke or death.^23,30,31

Carotid revascularization failed to reduce the risk of death—the total number of deaths within 10 years was not significantly reduced by immediate carotid endarterectomy compared with deferring the procedure.²

EVIDENCE SUPPORTING OPTIMAL MEDICAL MANAGEMENT

Optimal medical therapy mainly consists of antiplatelet therapy, blood pressure management, diabetic glycemic control, and statin therapy along with lifestyle changes including smoking cessation, exercise, and weight loss (Table 3).⁹ Detailed recommendations are provided in the American Heart Association/American Stroke Association guidelines for primary prevention of stroke.³²

Antiplatelet therapy has been shown to reduce the incidence of stroke by 25%. There is no added benefit in combining antiplatelet agents unless the patient has concomitant symptomatic coronary artery disease, recent coronary stenting, or severe peripheral artery disease.^33,34

Blood pressure control can reduce the incidence of stroke by 30% to 40%, and recent data suggest that drugs working on the renin-angiotensin system offer more benefit than beta-blockers for the same reduction in blood pressure.^34,35

Diabetic glycemic control is supported, as higher hemoglobin A_1c and fasting glucose values are associated with higher relative risk of stroke.^32,36,37 However, the stroke rate does not differ significantly between patients receiving intensive therapy and those receiving standard therapy.³⁴

Statins actually shrink carotid plaques and reduce the risk of stroke by 15% for each 10% reduction in low-density lipoprotein cholesterol. It is estimated that statin therapy confers a 30% relative risk reduction of stroke over 20 years.^34,38–41

Smoking increases the overall risk of stroke by 150%, making its cessation mandatory.⁴²

HIGH-RISK FEATURES FOR STROKE IN ASYMPTOMATIC CAROTID STENOSIS

Studies have tried to identify risk factors for stroke, so that patients at high risk could undergo revascularization and benefit from it. However, no well-defined high-risk features have yet been described that would identify patients who would benefit from early surgery.

For instance, no correlation has been found between age, sex, diabetes mellitus, lipid levels, or smoking and progression of disease.⁴³ In contrast, having either contralateral symptomatic carotid disease or contralateral total occlusion translated into a higher ipsilateral stroke risk.¹⁸ And in several studies, the 5-year risk of ipsilateral stroke was as high as 16.2% for those with 60% to 99% stenosis.^1,2,18,24,43

Features of the plaque itself

More recently, there has been a focus on plaque evaluation to predict outcomes.

Statins shrink carotid plaques and reduce the risk of stroke by 15% for each 10% reduction in LDL-C

Percent stenosis. An increased risk of death or stroke has been reported with higher degrees of stenosis or plaque progression.^44,45 The gross annual risk of ipsilateral stroke increases from 1.5% with stenosis of 60% to 70%, to 4.2% with stenosis of 71% to 90%, and to 7% with stenosis of 91% to 99%. Nevertheless, current data are insufficient to determine whether there is increasing benefit from surgery with increasing degree of stenosis in asymptomatic carotid disease.^1,3,24,44

Plaque progression translates to a 7.2% absolute increase in the incidence of stroke (1.1% if the plaque is stable vs 8.3% if the plaque is progressing). Interestingly, plaque progression to greater than 80% stenosis results in worse outcomes (relative risk 3.4, 95% CI 1.5–7.8) compared with the same level of stenosis without recent progression.³³

Intimal wall thickening of more than 1.15 mm confers a hazard ratio for stroke of 3 (95% CI 1.48–6.11).⁴⁶

Increased echolucency also confers a hazard ratio for stroke of 3 (95% CI 1.4–8.0).⁴⁶

A low gray-scale median (a surrogate of plaque composition) and plaque area have been identified as independent predictors of ipsilateral events.⁴⁴

Embolic signals on transcranial Doppler ultrasonography (Figure 1) have been associated with a hazard ratio for stroke of 2.54 over 2 years.⁴⁷

Carotid plaques predominantly composed of lipid-rich necrotic cores carry a higher risk of stroke (hazard ratio 7.2, 95% CI 1.12–46.20).⁴⁸

High tensile stress (circumferential wall tension divided by the intima-media thickness), and fibrous cap thickening (< 500 µm) predict plaque rupture.⁴⁹

Plaque ulceration. The risk of stroke increases with worsening degree of plaque ulceration: 0.4% per year for type A ulcerated plaques (small minimal excavations) compared with 12.5% for type B (large obvious excavations) and type C (multiple cavities or cavernous).⁵⁰

Low cerebrovascular reactivity. Perfusion studies such as cerebrovascular reactivity evaluate changes in cerebral blood flow in response to a stimulus such as inhaled carbon dioxide, breath-holding, or acetazolamide. This may provide a useful index of cerebral vascular function. For instance, low reactivity has been associated with ipsilateral ischemic events (odds ratio 14.4, 95% CI 2.63–78.74, P = .0021).^51,52 Silvestrini et al⁵³ reported that the incidence of ipsilateral cerebrovascular ischemic events was 4.1% per year in patients who had normal cerebral vasoreactivity during breath-holding, vs 13.9% in those with low cerebral reactivity.

BEST MEDICAL THERAPY, ALONE OR COMBINED WITH REVASCULARIZATION

For carotid revascularization to be a viable option for asymptomatic carotid stenosis, the morbidity and mortality rates associated with the operation must be less than the incidence of neurologic events in patients who do not undergo the operation.⁵⁴ An important caveat is that the longer a patient survives after carotid endarterectomy, the greater the potential benefit, since the adverse consequences of surgery are generally limited to the perioperative period.¹⁹

The current evidence regarding medical management of asymptomatic carotid stenosis suggests that the rate of ipsilateral stroke is now lower than it was in the control groups in the landmark trials.^{2,3,17,45,47,55,56} Ultimately, adherence to current best medical management takes priority over the decision to revascularize. The best current medical therapy includes, but is not limited to, antithrombotic therapy, statin therapy, blood pressure control, diabetes management, smoking cessation, and lifestyle changes (Table 3).

As noted above, stroke risk seems variable in the asymptomatic population according to the presence or absence of risk factors. Yet no well-defined “high-risk stroke profile” has been identified. Therefore, a patient-by-patient decision based on best available evidence should identify patients who may benefit from carotid revascularization. If asymptomatic carotid stenosis of 70% to 99% is found, factors that favor revascularization are male sex, younger age, and longer life expectancy (Figure 2).

For those with intermediate or high-risk surgical features, uncertainty exists in management since no studies have compared revascularization against medical management only in this group of patients.¹ However, data from high-risk cohorts had high enough complication rates in both intervention arms to question the benefit of revascularization over medical therapy.^20,21 Therefore, the individual perioperative risk of stroke, myocardial infarction, and death must be weighed against the potential benefit of revascularization for each patient.

If revascularization is pursued, studies have demonstrated that carotid artery stenting is not inferior to endarterectomy^15,16 in high-surgical-risk patients. However, the revascularization approach must be tailored to the patient profile, since stenting demonstrated a lower risk of periprocedural myocardial infarction but a higher risk of stroke compared with endarteretomy.²⁰

Finally, the current acceptable risks of perioperative stroke and death must be revised if revascularization is elected. Current data suggest that a lower threshold—around 1.4%—can be used.²⁰ Moreover, further guidelines must determine the impact of adding myocardial infarction to the tolerable perioperative risks, since it has been excluded from main trials and guidelines.²⁰

Carotid artery disease that is asymptomatic poses a dilemma: Should the patient undergo revascularization (surgical carotid endarterectomy or percutaneous stenting) or receive medical therapy alone?

On one hand, because one consequence of carotid atherosclerosis—ischemic stroke—can be devastating or deadly, many physicians and patients would rather “do something,” ie, proceed with surgery. Furthermore, several randomized trials^1–4 found carotid endarterectomy superior to medical therapy.

On the other hand, these trials were conducted in the 1990s. Surgery has improved since then, but so has medical therapy. And if we re-examine the data from the trials in terms of the absolute risk reduction and number needed to treat, as opposed to the relative risk reduction, surgery may appear less beneficial.

Needed is a way to identify patients who would benefit from surgery and those who would more likely be harmed. Research in that direction is ongoing.

Here, we present a simple algorithmic approach to managing asymptomatic carotid artery stenosis based on the patient’s age, sex, and life expectancy. Our approach is based on a review of the best available evidence.

UP TO 8% OF ADULTS HAVE STENOSIS

Stroke is the third largest cause of death in the United States and the leading cause of disability.⁵ From 10% to 15% of strokes are associated with carotid artery stenosis.^6,7

The prevalence of asymptomatic carotid disease, defined as stenosis greater than 50%, ranges from 4% to 8% in adults.⁸

However, major societies recommend against screening for carotid stenosis in the general population.^9–12 Similarly, the US Preventive Services Task Force also discourages the use of carotid auscultation as screening in the general population (Table 1).¹³ Generally, cases of asymptomatic carotid stenosis are diagnosed by ultrasonography after the patient’s physician happens to hear a bruit during a routine examination, during a preoperative assessment, or after the patient suffers a transient ischemic attack or stroke on the contralateral side.

CLASS II RECOMMENDATIONS FOR SURGERY OR STENTING

There are well-established guidelines for managing symptomatic carotid disease,¹⁴ based on evidence from the North American Symptomatic Carotid Endarterectomy Trial¹⁵ and the European Carotid Surgery Trial,¹⁶ both from 1998. But how to manage asymptomatic carotid disease remains uncertain.

If stenosis of the internal carotid artery is greater than 70% on ultrasonography, computed tomography, or magnetic resonance imaging, and if the risk of perioperative stroke and death is low (< 3%), current guidelines¹⁴ give carotid endarterectomy a class IIa recommendation (ie, evidence is conflicting, but the weight of evidence is in favor), and they give prophylactic carotid artery stenting with optimal medical treatment a class IIb recommendation (efficacy is less well established).⁵

But medical management has improved, and new data suggest that this improvement may override the minimal net benefit of intervention in some patients.¹⁷ Some authors suggest that it is best to use patient characteristics and imaging features to guide treatment.¹⁸

EVIDENCE TO SUPPORT CAROTID REVASCULARIZATION

Three major trials (Table 2) published nearly 20 years ago provide the foundation of the current guidelines:

• the Endarterectomy for Asymptomatic Carotid Atherosclerosis Study (ACAS)¹
• the Asymptomatic Carotid Surgery Trial (ACST)^2,3
• the Veterans Affairs (VA) Cooperative Study.⁴

A Cochrane review of these trials,¹⁹ where medical therapy consisted only of aspirin and little use of statin therapy, found that carotid endarterectomy reduced the rate of perioperative stroke or death or any subsequent stroke in the next 3 years by 31% (relative risk 69%, 95% confidence interval [CI] 0.57–0.83). “Perioperative” was defined as the period from randomization until 30 days after surgery in the surgical group and an equivalent period in the medical group.

Moreover, carotid endarterectomy reduced the rate of disabling or fatal nonperioperative stroke by 50% compared with medical management alone.^1,2,19 Patients who had contralateral symptomatic disease or who had undergone contralateral carotid endarterectomy seemed to benefit more from the procedure than those who had not.¹⁹

Also, the ACST investigators found that revascularization was associated with a reduction in contralateral strokes (which occurred in 39 vs 64 patients, P = .01) independent of contralateral symptoms or contralateral carotid endarterectomy.^2,3 The exact mechanism is unknown but could be related to better blood pressure control and risk factor modification after carotid endarterectomy.

Another factor supporting revascularization is that the outcomes of revascularization have improved over time. In 2010, the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)²⁰ reported a 30-day periprocedural incidence of death or stroke of only 1.4%, compared with 2.9% in the earlier landmark trials.

Stenting is a noninferior alternative

For patients who have asymptomatic stenosis greater than 80% on color duplex ultrasonography and a risk of stroke or death during carotid endarterectomy that is prohibitively high (> 3%), carotid stenting has proved to be a noninferior alternative.^21,22

The Stenting and Angioplasty With Protection of Patients With High Risk for Endarterectomy (SAPPHIRE) trial²¹ reported a risk of death, stroke, or myocardial infarction of about 5% at 30 days and 10% at 1 year after stenting. A recent observational study revealed lower perioperative complication rates, with a risk of death or stroke of about 3%, which satisfy current guideline requirements.²³

To be deemed at high surgical risk and therefore eligible for the SAPPHIRE trial,²¹ patients had to have clinically significant cardiac disease, severe pulmonary disease, contralateral carotid occlusion, contralateral laryngeal-nerve palsy, recurrent stenosis after carotid endarterectomy, previous radical neck surgery or radiation therapy to the neck, or age greater than 80.

EVIDENCE AGAINST CAROTID REVASCULARIZATION

Although carotid revascularization has evidence to support it, further interpretation of the data may lessen its apparent benefits.

Small absolute benefit, high number needed to treat

If we compare the relative risk reduction for the outcome of perioperative death or any stroke over 5 years (30% to 50%) vs the absolute risk reduction (4% to 5.9%), revascularization seems less attractive.¹⁹

Relative risk reduction in death or stroke with carotid surgery is 30%–50%; absolute risk reduction is 4%–5.9%

The benefit may be further diminished if we consider only strokes related to large vessels, since up to 45% of strokes in patients with carotid disease are lacunar or cardioembolic.²⁴ Assessing for prevention of large-vessel stroke using the ACAS data, the benefit of carotid endarterectomy for prevention of stroke is further decreased to a 3.5% absolute risk reduction, and the number needed to treat for 2 years increases from 62 to 111.^24,25 Nevertheless, revascularization is necessary in appropriately selected patients, as a cerebrovascular event can cause life-altering changes to a patient’s cognitive, emotional, and physical condition.²⁶

Medical therapy—and surgery—are evolving

The optimal medical management used in the landmark studies was significantly different from what is currently recommended. The ACAS trial¹⁸ used only aspirin as optimal medical management, with no mention of statins. In the ACST trial,^2,3 the use of statins increased over time, from 7% to 11% at the beginning of the trial to 80% to 82% at the end.

On the other hand, the ACAS¹ surgeons were required to have an excellent safety record to participate. This might have compromised the trial’s validity or our ability to generalize its conclusions.

Recent data from Abbott¹⁷ suggested a loss of a statistically significant surgical advantage in prevention of ipsilateral stroke and transient ischemic attack from the early 1990s. This is most likely explained by improved medical therapy, since there was a 22% increase in baseline proportion of patients receiving antiplatelet therapy from 1985 to 2007, with 60% of patients taking antihypertensive drugs and 30% of patients taking lipid-lowering drugs. Moreover, since 2001, the annual rates of ipsilateral stroke in patients receiving medical management alone fell below those of patients who underwent carotid endarterectomy in the ACAS trial.

The analysis by Abbott¹⁷ has major limitations: inclusion of small studies, many crossover patients, and heterogeneity. In support of this allegation, a small trial (33 patients) reported a risk of stroke ipsilateral to an asymptomatic carotid stenosis as low as 0.34% per year.²⁵ Even when contrasting the outcomes of medical therapy against those of current carotid endarterectomy, in which the rate of perioperative stroke and death have fallen to 0.88% to 1.7%,^17,27,28 there is concern that the risk associated with surgery may outweigh the long-term benefit.

Flaws in the landmark trials

Beyond the debate of the questionable benefit of revascularization, well-defined flaws in the landmark trials weaken or limit their influence on current treatment guidelines and protocols for deciding whether to revascularize.

No significant benefit was found for patients over age 75.^2,3 This was thought to be due to decreased life expectancy, since the benefit from revascularization becomes significant after 3 years from intervention.^1–3 Also, studies have shown that increasing age is associated with a higher risk of perioperative stroke and death.^20,21

Women showed no benefit at 5 years and only a trend toward benefit at 10 years (P = .05),² likely from a higher rate of periprocedural strokes.

Blacks and Hispanics were underrepresented in the landmark studies,¹⁹ while one observational study reported a higher incidence of in-hospital stroke after carotid endarterectomy in black patients (6.6%) than in white patients (2%).²⁹

When associated with contralateral carotid occlusion, carotid endarterectomy carries a higher risk of perioperative stroke or death.^23,30,31

Carotid revascularization failed to reduce the risk of death—the total number of deaths within 10 years was not significantly reduced by immediate carotid endarterectomy compared with deferring the procedure.²

EVIDENCE SUPPORTING OPTIMAL MEDICAL MANAGEMENT

Optimal medical therapy mainly consists of antiplatelet therapy, blood pressure management, diabetic glycemic control, and statin therapy along with lifestyle changes including smoking cessation, exercise, and weight loss (Table 3).⁹ Detailed recommendations are provided in the American Heart Association/American Stroke Association guidelines for primary prevention of stroke.³²

Antiplatelet therapy has been shown to reduce the incidence of stroke by 25%. There is no added benefit in combining antiplatelet agents unless the patient has concomitant symptomatic coronary artery disease, recent coronary stenting, or severe peripheral artery disease.^33,34

Blood pressure control can reduce the incidence of stroke by 30% to 40%, and recent data suggest that drugs working on the renin-angiotensin system offer more benefit than beta-blockers for the same reduction in blood pressure.^34,35

Diabetic glycemic control is supported, as higher hemoglobin A_1c and fasting glucose values are associated with higher relative risk of stroke.^32,36,37 However, the stroke rate does not differ significantly between patients receiving intensive therapy and those receiving standard therapy.³⁴

Statins actually shrink carotid plaques and reduce the risk of stroke by 15% for each 10% reduction in low-density lipoprotein cholesterol. It is estimated that statin therapy confers a 30% relative risk reduction of stroke over 20 years.^34,38–41

Smoking increases the overall risk of stroke by 150%, making its cessation mandatory.⁴²

HIGH-RISK FEATURES FOR STROKE IN ASYMPTOMATIC CAROTID STENOSIS

Studies have tried to identify risk factors for stroke, so that patients at high risk could undergo revascularization and benefit from it. However, no well-defined high-risk features have yet been described that would identify patients who would benefit from early surgery.

For instance, no correlation has been found between age, sex, diabetes mellitus, lipid levels, or smoking and progression of disease.⁴³ In contrast, having either contralateral symptomatic carotid disease or contralateral total occlusion translated into a higher ipsilateral stroke risk.¹⁸ And in several studies, the 5-year risk of ipsilateral stroke was as high as 16.2% for those with 60% to 99% stenosis.^1,2,18,24,43

Features of the plaque itself

More recently, there has been a focus on plaque evaluation to predict outcomes.

Statins shrink carotid plaques and reduce the risk of stroke by 15% for each 10% reduction in LDL-C

Percent stenosis. An increased risk of death or stroke has been reported with higher degrees of stenosis or plaque progression.^44,45 The gross annual risk of ipsilateral stroke increases from 1.5% with stenosis of 60% to 70%, to 4.2% with stenosis of 71% to 90%, and to 7% with stenosis of 91% to 99%. Nevertheless, current data are insufficient to determine whether there is increasing benefit from surgery with increasing degree of stenosis in asymptomatic carotid disease.^1,3,24,44

Plaque progression translates to a 7.2% absolute increase in the incidence of stroke (1.1% if the plaque is stable vs 8.3% if the plaque is progressing). Interestingly, plaque progression to greater than 80% stenosis results in worse outcomes (relative risk 3.4, 95% CI 1.5–7.8) compared with the same level of stenosis without recent progression.³³

Intimal wall thickening of more than 1.15 mm confers a hazard ratio for stroke of 3 (95% CI 1.48–6.11).⁴⁶

Increased echolucency also confers a hazard ratio for stroke of 3 (95% CI 1.4–8.0).⁴⁶

A low gray-scale median (a surrogate of plaque composition) and plaque area have been identified as independent predictors of ipsilateral events.⁴⁴

Embolic signals on transcranial Doppler ultrasonography (Figure 1) have been associated with a hazard ratio for stroke of 2.54 over 2 years.⁴⁷

Carotid plaques predominantly composed of lipid-rich necrotic cores carry a higher risk of stroke (hazard ratio 7.2, 95% CI 1.12–46.20).⁴⁸

High tensile stress (circumferential wall tension divided by the intima-media thickness), and fibrous cap thickening (< 500 µm) predict plaque rupture.⁴⁹

Plaque ulceration. The risk of stroke increases with worsening degree of plaque ulceration: 0.4% per year for type A ulcerated plaques (small minimal excavations) compared with 12.5% for type B (large obvious excavations) and type C (multiple cavities or cavernous).⁵⁰

Low cerebrovascular reactivity. Perfusion studies such as cerebrovascular reactivity evaluate changes in cerebral blood flow in response to a stimulus such as inhaled carbon dioxide, breath-holding, or acetazolamide. This may provide a useful index of cerebral vascular function. For instance, low reactivity has been associated with ipsilateral ischemic events (odds ratio 14.4, 95% CI 2.63–78.74, P = .0021).^51,52 Silvestrini et al⁵³ reported that the incidence of ipsilateral cerebrovascular ischemic events was 4.1% per year in patients who had normal cerebral vasoreactivity during breath-holding, vs 13.9% in those with low cerebral reactivity.

BEST MEDICAL THERAPY, ALONE OR COMBINED WITH REVASCULARIZATION

For carotid revascularization to be a viable option for asymptomatic carotid stenosis, the morbidity and mortality rates associated with the operation must be less than the incidence of neurologic events in patients who do not undergo the operation.⁵⁴ An important caveat is that the longer a patient survives after carotid endarterectomy, the greater the potential benefit, since the adverse consequences of surgery are generally limited to the perioperative period.¹⁹

The current evidence regarding medical management of asymptomatic carotid stenosis suggests that the rate of ipsilateral stroke is now lower than it was in the control groups in the landmark trials.^{2,3,17,45,47,55,56} Ultimately, adherence to current best medical management takes priority over the decision to revascularize. The best current medical therapy includes, but is not limited to, antithrombotic therapy, statin therapy, blood pressure control, diabetes management, smoking cessation, and lifestyle changes (Table 3).

As noted above, stroke risk seems variable in the asymptomatic population according to the presence or absence of risk factors. Yet no well-defined “high-risk stroke profile” has been identified. Therefore, a patient-by-patient decision based on best available evidence should identify patients who may benefit from carotid revascularization. If asymptomatic carotid stenosis of 70% to 99% is found, factors that favor revascularization are male sex, younger age, and longer life expectancy (Figure 2).

For those with intermediate or high-risk surgical features, uncertainty exists in management since no studies have compared revascularization against medical management only in this group of patients.¹ However, data from high-risk cohorts had high enough complication rates in both intervention arms to question the benefit of revascularization over medical therapy.^20,21 Therefore, the individual perioperative risk of stroke, myocardial infarction, and death must be weighed against the potential benefit of revascularization for each patient.

If revascularization is pursued, studies have demonstrated that carotid artery stenting is not inferior to endarterectomy^15,16 in high-surgical-risk patients. However, the revascularization approach must be tailored to the patient profile, since stenting demonstrated a lower risk of periprocedural myocardial infarction but a higher risk of stroke compared with endarteretomy.²⁰

Finally, the current acceptable risks of perioperative stroke and death must be revised if revascularization is elected. Current data suggest that a lower threshold—around 1.4%—can be used.²⁰ Moreover, further guidelines must determine the impact of adding myocardial infarction to the tolerable perioperative risks, since it has been excluded from main trials and guidelines.²⁰

Alcohol use disorder (AUD) is a mosaic of psychiatric and medical symptoms. Alcoholic liver disease (ALD) in its acute and chronic forms is a common clinical consequence of long-standing AUD. Patients with ALD require specialized care from pro­fessionals in addiction, gastroenterology, and psychiatry. However, medical specialists treating ALD might not regularly consider medi­cations to treat AUD because of their limited experience with the drugs or the lack of studies in patients with significant liver disease.¹ Similarly, psychiatrists might be reticent to prescribe medications for AUD, fearing that liver disease will be made worse or that they will cause other medical complications. As a result, patients with ALD might not receive care that could help treat their AUD (Box).

Given the high worldwide prevalence and morbidity of ALD,² gen­eral and subspecialized psychiatrists routinely evaluate patients with AUD in and out of the hospital. This article aims to equip a psychia­trist with:
   • a practical understanding of the natural history and categorization of ALD
   • basic skills to detect symptoms of ALD
   • preparation to collaborate with medical colleagues in multidisciplinary management of co-occurring AUD and ALD
   • a summary of the pharmacotherapeutics of AUD, with emphasis on patients with clinically apparent ALD.

Categorization and clinical features
Alcoholic liver damage encompasses a spectrum of disorders, including alcoholic fatty liver, acute alcohol hepatitis (AH), and cirrhosis following varying durations and patterns of alcohol use. Manifestations of ALD vary from asymptomatic fatty liver with minimal liver enzyme eleva­tion to severe acute AH with jaundice, coagulopathy, and high short-term mor­tality (Table 1). Symptoms seen in patients with AH include fever, abdominal pain, anorexia, jaundice, leukocytosis, and coagulopathy.³

All patients who drink heavily or suffer with AUD are at risk of developing AH; women and binge drinkers are particu­larly vulnerable.⁴ Liver dysfunction and malnutrition in ALD patients compromise the immune system, increasing the risk of infection. Patients hospitalized with AH have a 10% to 30% risk of inpatient mor­tality; their 1- and 2-month post-discharge survival is 50% to 65%, largely determined by whether the patient can maintain sobri­ety.⁵ Psychiatrists’ contribution to ALD treatment therefore has the potential to save lives.

Screening and detection of ALD
Because of the high mortality associated with AH and cirrhosis, symptom recogni­tion and collaborative medical and psy­chiatric management are critical (Table 2). A psychiatrist evaluating a jaun­diced patient who continues to drink should arrange urgent medical evaluation. While gathering a history, mental health providers might hear a patient refer to symptoms of gastrointestinal bleeding (vomiting blood, bloody or dark stool), painful abdominal distension, fevers, or confusion that should prompt a referral to a gastroenterologist or the emergency department. Testing for uri­nary ethyl glucuronide—a direct metabolite of ethanol that can be detected for as long as 90 hours after ethanol ingestion—is use­ful in detecting alcohol use in the past 4 or 5 days.

Medical management of ALD
Corticosteroids are a mainstay in pharma­cotherapy for severe AH. There is evidence for improved outcomes in patients with severe AH treated with prednisolone for 4 to 6 weeks.⁵ Prognostic models such as the Maddrey’s Discriminant Function, Lille Model, and the MELD score help determine the need for steroid use and identify high-risk patients. Patients with active infection or bleeding are not a candidate for steroid treatment. An experienced gastroenterolo­gist or hepatologist should initiate medical intervention after thorough evaluation.

Liver transplantation. A select group of patients with refractory liver failure are con­sidered for liver transplantation. Although transplant programs differ in their criteria for organ listing, many require patients to demonstrate at least 6 months of verified abstinence from alcohol and illicit drugs as well as adherence to a formal AUD treat­ment and rehabilitation plan. The patient’s psychological health and prognosis for sus­tained sobriety are central to candidacy for organ listing, which highlights the key role of psychiatrists.

Further considerations. Thiamine and folate often are given to patients with ALD. Abdominal imaging and screening for HIV and viral hepatitis—identified in 10% to 20% of ALD patients—is routine. Alcohol absti­nence remains central to survival because relapse increases the risk of recurrent, severe liver disease. Regrettably, many physical symptoms of liver disease, such as portal hypertension, ascites, and jaundice, can take months to improve with abstinence.

Treating AUD in patients with ALD
Successful treatment is multifaceted and includes more than just medications. Initial management often includes addressing alcohol withdrawal in dependent patients.⁶

Behavioral interventions are effective and indispensable components in prevent­ing relapse,⁷ including a written relapse prevention plan that formally outlines the patient’s commitment to change, identi­fies triggers, and outlines a discrete plan of action. Primary psychiatric pathology, including depression and anxiety, often are comorbid with AUD; concurrent treatment of these disorders could improve patient outcomes.⁸

Benzodiazepines often are used during acute alcohol withdrawal. They should not be used for relapse prevention in ALD because of their additive interactions with alcohol, cognitive and psychomotor side effects, and abuse potential.^9,10 Many of these drugs are cleared by the liver and generally are not recommended for use in patients with ALD.

Other agents, further considerations. Drug trials in AUD largely have been con­ducted in small, heterogeneous populations and revealed modest and, at times, con­flicting drug effect sizes.^6,11,12 The placebo effect among the AUD population is pro­nounced.^6,7,13 Despite these caveats, several agents have been studied and validated by the FDA to treat AUD. Additional agents with promising pilot data are being inves­tigated. Table 3^{1,7,10,11,13-43} summa­rizes drugs used to treat AUD—those with and without FDA approval—with a focus on how they might be used in patients with ALD. Of note, several of these agents do not rely on the liver for metabolism or excretion.

That being said, the AUD treatment liter­ature suggests that specific drugs might be more useful in patients with varying sever­ity of disease and during different phases of recovery:
   • Acamprosate has been found to be effective in supporting abstinence in sober patients.^14,44
   • Naltrexone has been shown to be useful in patients with severe alcohol cravings. By modulating alcohol’s rewarding effects, naltrexone also reduces heavy alcohol consumption in patients who are drinking.^14,15,44
   • Disulfiram generally is not recommended for use in patients with clinically apparent hepatic insufficiency, such as decompensated cirrhosis or preexisting jaundice.

Although alcohol abstinence remains the treatment goal and a requirement for liver transplant, providers must recognize that some patients might not be able to maintain long-term sobriety. Therefore, harm reduc­tion models are important companions to abstinence-only models of AUD treatment.⁴⁵ The array of behavioral, pharmacologi­cal, and philosophical approaches to AUD treatment underlines the need for an indi­vidualized approach to relapse prevention.

Collaboration between medicine and psychiatry
When AUD and ALD are comorbid, psy­chiatrists might worry about making the patient’s medical condition worse by pre­scribing additional psychoactive medica­tions—particularly ones that are cleared by the liver. Remember that AUD confers a substantial mortality rate that is more than 3 times that of the general population, along with severe medical⁴⁶ and psycho­social³¹ effects. Although prescribers must remain vigilant for adverse drug effects, medications easily can be blamed for what might be the natural progression and symp­toms of AUD in patients with ALD.²⁶ This erroneous conclusion can lead to premature medication discontinuation and under-treatment of AUD.

In the end, keeping the patient sober and mentally well might be more beneficial than eliminating the burden of any medica­tion side effects. Collaborative medical and psychiatric management of ALD patients can ensure that clinicians properly weigh the risks, benefits, and duration of treat­ment unique to each patient.

Starting AUD treatment promptly after alcohol relapse is essential and entails a multidisciplinary effort between medicine and psychiatry, both in and out of the hos­pital. Because the relapsing, ill ALD patient most often will be admitted to a medical specialist, AUD might not receive enough attention during the medical admission. Psychiatrists can help in initiating AUD treatment in the acute medical setting, which has been shown to improve the out­patient course.⁶ For medically stable ALD patients admitted for inpatient psychiatric care or presenting a clinic, the mental health clinician should be aware of key laboratory and physical exam findings.

Bottom Line
Patients with alcoholic liver disease (ALD) require collaborative care from specialists in addiction, gastroenterology, and psychiatry. Psychiatrists have a role in identifying signs of ALD, prescribing medication to treat alcohol use disorder, and encouraging abstinence. There is some evidence supporting specific medications for varying severity of disease and different phases of recovery. Pharmacotherapy decisions should be made case by case.

Related Resources
• Khan A, Tansel A, White DL, et al. Efficacy of psychosocial interventions in inducing and maintaining alcohol abstinence in patients with chronic liver disease: a systematic review [published online August 6, 2015]. Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2015.07.047.
• Vuittonet CL, Halse M, Leggio L, et al. Pharmacotherapy for alcoholic patients with alcoholic liver disease. Am J Health Syst Pharm. 2014;71(15):1265-1276.

Drug Brand Names
Acamprosate • Campral                       
Baclofen • Lioresal                              
Disulfiram • Antabuse                          
Gabapentin • Neurontin                       
Naltrexone • ReVia, Vivitrol
Pentoxifylline • Trental
Prednisolone • Prelone
Rifaximin • Xifaxan
Topiramate • Topamax

Disclosures
Dr. Winder and Dr. Mellinger report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products. Dr. Fontana receives research funding from Bristol Myers Squibb, Gilead, and Janssen and consults for the Chronic Liver Disease Foundation.

Alcohol use disorder (AUD) is a mosaic of psychiatric and medical symptoms. Alcoholic liver disease (ALD) in its acute and chronic forms is a common clinical consequence of long-standing AUD. Patients with ALD require specialized care from pro­fessionals in addiction, gastroenterology, and psychiatry. However, medical specialists treating ALD might not regularly consider medi­cations to treat AUD because of their limited experience with the drugs or the lack of studies in patients with significant liver disease.¹ Similarly, psychiatrists might be reticent to prescribe medications for AUD, fearing that liver disease will be made worse or that they will cause other medical complications. As a result, patients with ALD might not receive care that could help treat their AUD (Box).

Given the high worldwide prevalence and morbidity of ALD,² gen­eral and subspecialized psychiatrists routinely evaluate patients with AUD in and out of the hospital. This article aims to equip a psychia­trist with:
   • a practical understanding of the natural history and categorization of ALD
   • basic skills to detect symptoms of ALD
   • preparation to collaborate with medical colleagues in multidisciplinary management of co-occurring AUD and ALD
   • a summary of the pharmacotherapeutics of AUD, with emphasis on patients with clinically apparent ALD.

Categorization and clinical features
Alcoholic liver damage encompasses a spectrum of disorders, including alcoholic fatty liver, acute alcohol hepatitis (AH), and cirrhosis following varying durations and patterns of alcohol use. Manifestations of ALD vary from asymptomatic fatty liver with minimal liver enzyme eleva­tion to severe acute AH with jaundice, coagulopathy, and high short-term mor­tality (Table 1). Symptoms seen in patients with AH include fever, abdominal pain, anorexia, jaundice, leukocytosis, and coagulopathy.³

All patients who drink heavily or suffer with AUD are at risk of developing AH; women and binge drinkers are particu­larly vulnerable.⁴ Liver dysfunction and malnutrition in ALD patients compromise the immune system, increasing the risk of infection. Patients hospitalized with AH have a 10% to 30% risk of inpatient mor­tality; their 1- and 2-month post-discharge survival is 50% to 65%, largely determined by whether the patient can maintain sobri­ety.⁵ Psychiatrists’ contribution to ALD treatment therefore has the potential to save lives.

Screening and detection of ALD
Because of the high mortality associated with AH and cirrhosis, symptom recogni­tion and collaborative medical and psy­chiatric management are critical (Table 2). A psychiatrist evaluating a jaun­diced patient who continues to drink should arrange urgent medical evaluation. While gathering a history, mental health providers might hear a patient refer to symptoms of gastrointestinal bleeding (vomiting blood, bloody or dark stool), painful abdominal distension, fevers, or confusion that should prompt a referral to a gastroenterologist or the emergency department. Testing for uri­nary ethyl glucuronide—a direct metabolite of ethanol that can be detected for as long as 90 hours after ethanol ingestion—is use­ful in detecting alcohol use in the past 4 or 5 days.

Medical management of ALD
Corticosteroids are a mainstay in pharma­cotherapy for severe AH. There is evidence for improved outcomes in patients with severe AH treated with prednisolone for 4 to 6 weeks.⁵ Prognostic models such as the Maddrey’s Discriminant Function, Lille Model, and the MELD score help determine the need for steroid use and identify high-risk patients. Patients with active infection or bleeding are not a candidate for steroid treatment. An experienced gastroenterolo­gist or hepatologist should initiate medical intervention after thorough evaluation.

Liver transplantation. A select group of patients with refractory liver failure are con­sidered for liver transplantation. Although transplant programs differ in their criteria for organ listing, many require patients to demonstrate at least 6 months of verified abstinence from alcohol and illicit drugs as well as adherence to a formal AUD treat­ment and rehabilitation plan. The patient’s psychological health and prognosis for sus­tained sobriety are central to candidacy for organ listing, which highlights the key role of psychiatrists.

Further considerations. Thiamine and folate often are given to patients with ALD. Abdominal imaging and screening for HIV and viral hepatitis—identified in 10% to 20% of ALD patients—is routine. Alcohol absti­nence remains central to survival because relapse increases the risk of recurrent, severe liver disease. Regrettably, many physical symptoms of liver disease, such as portal hypertension, ascites, and jaundice, can take months to improve with abstinence.

Treating AUD in patients with ALD
Successful treatment is multifaceted and includes more than just medications. Initial management often includes addressing alcohol withdrawal in dependent patients.⁶

Behavioral interventions are effective and indispensable components in prevent­ing relapse,⁷ including a written relapse prevention plan that formally outlines the patient’s commitment to change, identi­fies triggers, and outlines a discrete plan of action. Primary psychiatric pathology, including depression and anxiety, often are comorbid with AUD; concurrent treatment of these disorders could improve patient outcomes.⁸

Benzodiazepines often are used during acute alcohol withdrawal. They should not be used for relapse prevention in ALD because of their additive interactions with alcohol, cognitive and psychomotor side effects, and abuse potential.^9,10 Many of these drugs are cleared by the liver and generally are not recommended for use in patients with ALD.

Other agents, further considerations. Drug trials in AUD largely have been con­ducted in small, heterogeneous populations and revealed modest and, at times, con­flicting drug effect sizes.^6,11,12 The placebo effect among the AUD population is pro­nounced.^6,7,13 Despite these caveats, several agents have been studied and validated by the FDA to treat AUD. Additional agents with promising pilot data are being inves­tigated. Table 3^{1,7,10,11,13-43} summa­rizes drugs used to treat AUD—those with and without FDA approval—with a focus on how they might be used in patients with ALD. Of note, several of these agents do not rely on the liver for metabolism or excretion.

That being said, the AUD treatment liter­ature suggests that specific drugs might be more useful in patients with varying sever­ity of disease and during different phases of recovery:
   • Acamprosate has been found to be effective in supporting abstinence in sober patients.^14,44
   • Naltrexone has been shown to be useful in patients with severe alcohol cravings. By modulating alcohol’s rewarding effects, naltrexone also reduces heavy alcohol consumption in patients who are drinking.^14,15,44
   • Disulfiram generally is not recommended for use in patients with clinically apparent hepatic insufficiency, such as decompensated cirrhosis or preexisting jaundice.

Although alcohol abstinence remains the treatment goal and a requirement for liver transplant, providers must recognize that some patients might not be able to maintain long-term sobriety. Therefore, harm reduc­tion models are important companions to abstinence-only models of AUD treatment.⁴⁵ The array of behavioral, pharmacologi­cal, and philosophical approaches to AUD treatment underlines the need for an indi­vidualized approach to relapse prevention.

Collaboration between medicine and psychiatry
When AUD and ALD are comorbid, psy­chiatrists might worry about making the patient’s medical condition worse by pre­scribing additional psychoactive medica­tions—particularly ones that are cleared by the liver. Remember that AUD confers a substantial mortality rate that is more than 3 times that of the general population, along with severe medical⁴⁶ and psycho­social³¹ effects. Although prescribers must remain vigilant for adverse drug effects, medications easily can be blamed for what might be the natural progression and symp­toms of AUD in patients with ALD.²⁶ This erroneous conclusion can lead to premature medication discontinuation and under-treatment of AUD.

In the end, keeping the patient sober and mentally well might be more beneficial than eliminating the burden of any medica­tion side effects. Collaborative medical and psychiatric management of ALD patients can ensure that clinicians properly weigh the risks, benefits, and duration of treat­ment unique to each patient.

Starting AUD treatment promptly after alcohol relapse is essential and entails a multidisciplinary effort between medicine and psychiatry, both in and out of the hos­pital. Because the relapsing, ill ALD patient most often will be admitted to a medical specialist, AUD might not receive enough attention during the medical admission. Psychiatrists can help in initiating AUD treatment in the acute medical setting, which has been shown to improve the out­patient course.⁶ For medically stable ALD patients admitted for inpatient psychiatric care or presenting a clinic, the mental health clinician should be aware of key laboratory and physical exam findings.

Bottom Line
Patients with alcoholic liver disease (ALD) require collaborative care from specialists in addiction, gastroenterology, and psychiatry. Psychiatrists have a role in identifying signs of ALD, prescribing medication to treat alcohol use disorder, and encouraging abstinence. There is some evidence supporting specific medications for varying severity of disease and different phases of recovery. Pharmacotherapy decisions should be made case by case.

Related Resources
• Khan A, Tansel A, White DL, et al. Efficacy of psychosocial interventions in inducing and maintaining alcohol abstinence in patients with chronic liver disease: a systematic review [published online August 6, 2015]. Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2015.07.047.
• Vuittonet CL, Halse M, Leggio L, et al. Pharmacotherapy for alcoholic patients with alcoholic liver disease. Am J Health Syst Pharm. 2014;71(15):1265-1276.

Drug Brand Names
Acamprosate • Campral                       
Baclofen • Lioresal                              
Disulfiram • Antabuse                          
Gabapentin • Neurontin                       
Naltrexone • ReVia, Vivitrol
Pentoxifylline • Trental
Prednisolone • Prelone
Rifaximin • Xifaxan
Topiramate • Topamax

Disclosures
Dr. Winder and Dr. Mellinger report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products. Dr. Fontana receives research funding from Bristol Myers Squibb, Gilead, and Janssen and consults for the Chronic Liver Disease Foundation.

Alcohol use disorder (AUD) is a mosaic of psychiatric and medical symptoms. Alcoholic liver disease (ALD) in its acute and chronic forms is a common clinical consequence of long-standing AUD. Patients with ALD require specialized care from pro­fessionals in addiction, gastroenterology, and psychiatry. However, medical specialists treating ALD might not regularly consider medi­cations to treat AUD because of their limited experience with the drugs or the lack of studies in patients with significant liver disease.¹ Similarly, psychiatrists might be reticent to prescribe medications for AUD, fearing that liver disease will be made worse or that they will cause other medical complications. As a result, patients with ALD might not receive care that could help treat their AUD (Box).

Given the high worldwide prevalence and morbidity of ALD,² gen­eral and subspecialized psychiatrists routinely evaluate patients with AUD in and out of the hospital. This article aims to equip a psychia­trist with:
   • a practical understanding of the natural history and categorization of ALD
   • basic skills to detect symptoms of ALD
   • preparation to collaborate with medical colleagues in multidisciplinary management of co-occurring AUD and ALD
   • a summary of the pharmacotherapeutics of AUD, with emphasis on patients with clinically apparent ALD.

Categorization and clinical features
Alcoholic liver damage encompasses a spectrum of disorders, including alcoholic fatty liver, acute alcohol hepatitis (AH), and cirrhosis following varying durations and patterns of alcohol use. Manifestations of ALD vary from asymptomatic fatty liver with minimal liver enzyme eleva­tion to severe acute AH with jaundice, coagulopathy, and high short-term mor­tality (Table 1). Symptoms seen in patients with AH include fever, abdominal pain, anorexia, jaundice, leukocytosis, and coagulopathy.³

All patients who drink heavily or suffer with AUD are at risk of developing AH; women and binge drinkers are particu­larly vulnerable.⁴ Liver dysfunction and malnutrition in ALD patients compromise the immune system, increasing the risk of infection. Patients hospitalized with AH have a 10% to 30% risk of inpatient mor­tality; their 1- and 2-month post-discharge survival is 50% to 65%, largely determined by whether the patient can maintain sobri­ety.⁵ Psychiatrists’ contribution to ALD treatment therefore has the potential to save lives.

Screening and detection of ALD
Because of the high mortality associated with AH and cirrhosis, symptom recogni­tion and collaborative medical and psy­chiatric management are critical (Table 2). A psychiatrist evaluating a jaun­diced patient who continues to drink should arrange urgent medical evaluation. While gathering a history, mental health providers might hear a patient refer to symptoms of gastrointestinal bleeding (vomiting blood, bloody or dark stool), painful abdominal distension, fevers, or confusion that should prompt a referral to a gastroenterologist or the emergency department. Testing for uri­nary ethyl glucuronide—a direct metabolite of ethanol that can be detected for as long as 90 hours after ethanol ingestion—is use­ful in detecting alcohol use in the past 4 or 5 days.

Medical management of ALD
Corticosteroids are a mainstay in pharma­cotherapy for severe AH. There is evidence for improved outcomes in patients with severe AH treated with prednisolone for 4 to 6 weeks.⁵ Prognostic models such as the Maddrey’s Discriminant Function, Lille Model, and the MELD score help determine the need for steroid use and identify high-risk patients. Patients with active infection or bleeding are not a candidate for steroid treatment. An experienced gastroenterolo­gist or hepatologist should initiate medical intervention after thorough evaluation.

Liver transplantation. A select group of patients with refractory liver failure are con­sidered for liver transplantation. Although transplant programs differ in their criteria for organ listing, many require patients to demonstrate at least 6 months of verified abstinence from alcohol and illicit drugs as well as adherence to a formal AUD treat­ment and rehabilitation plan. The patient’s psychological health and prognosis for sus­tained sobriety are central to candidacy for organ listing, which highlights the key role of psychiatrists.

Further considerations. Thiamine and folate often are given to patients with ALD. Abdominal imaging and screening for HIV and viral hepatitis—identified in 10% to 20% of ALD patients—is routine. Alcohol absti­nence remains central to survival because relapse increases the risk of recurrent, severe liver disease. Regrettably, many physical symptoms of liver disease, such as portal hypertension, ascites, and jaundice, can take months to improve with abstinence.

Treating AUD in patients with ALD
Successful treatment is multifaceted and includes more than just medications. Initial management often includes addressing alcohol withdrawal in dependent patients.⁶

Behavioral interventions are effective and indispensable components in prevent­ing relapse,⁷ including a written relapse prevention plan that formally outlines the patient’s commitment to change, identi­fies triggers, and outlines a discrete plan of action. Primary psychiatric pathology, including depression and anxiety, often are comorbid with AUD; concurrent treatment of these disorders could improve patient outcomes.⁸

Benzodiazepines often are used during acute alcohol withdrawal. They should not be used for relapse prevention in ALD because of their additive interactions with alcohol, cognitive and psychomotor side effects, and abuse potential.^9,10 Many of these drugs are cleared by the liver and generally are not recommended for use in patients with ALD.

Other agents, further considerations. Drug trials in AUD largely have been con­ducted in small, heterogeneous populations and revealed modest and, at times, con­flicting drug effect sizes.^6,11,12 The placebo effect among the AUD population is pro­nounced.^6,7,13 Despite these caveats, several agents have been studied and validated by the FDA to treat AUD. Additional agents with promising pilot data are being inves­tigated. Table 3^{1,7,10,11,13-43} summa­rizes drugs used to treat AUD—those with and without FDA approval—with a focus on how they might be used in patients with ALD. Of note, several of these agents do not rely on the liver for metabolism or excretion.

That being said, the AUD treatment liter­ature suggests that specific drugs might be more useful in patients with varying sever­ity of disease and during different phases of recovery:
   • Acamprosate has been found to be effective in supporting abstinence in sober patients.^14,44
   • Naltrexone has been shown to be useful in patients with severe alcohol cravings. By modulating alcohol’s rewarding effects, naltrexone also reduces heavy alcohol consumption in patients who are drinking.^14,15,44
   • Disulfiram generally is not recommended for use in patients with clinically apparent hepatic insufficiency, such as decompensated cirrhosis or preexisting jaundice.

Although alcohol abstinence remains the treatment goal and a requirement for liver transplant, providers must recognize that some patients might not be able to maintain long-term sobriety. Therefore, harm reduc­tion models are important companions to abstinence-only models of AUD treatment.⁴⁵ The array of behavioral, pharmacologi­cal, and philosophical approaches to AUD treatment underlines the need for an indi­vidualized approach to relapse prevention.

Collaboration between medicine and psychiatry
When AUD and ALD are comorbid, psy­chiatrists might worry about making the patient’s medical condition worse by pre­scribing additional psychoactive medica­tions—particularly ones that are cleared by the liver. Remember that AUD confers a substantial mortality rate that is more than 3 times that of the general population, along with severe medical⁴⁶ and psycho­social³¹ effects. Although prescribers must remain vigilant for adverse drug effects, medications easily can be blamed for what might be the natural progression and symp­toms of AUD in patients with ALD.²⁶ This erroneous conclusion can lead to premature medication discontinuation and under-treatment of AUD.

In the end, keeping the patient sober and mentally well might be more beneficial than eliminating the burden of any medica­tion side effects. Collaborative medical and psychiatric management of ALD patients can ensure that clinicians properly weigh the risks, benefits, and duration of treat­ment unique to each patient.

Starting AUD treatment promptly after alcohol relapse is essential and entails a multidisciplinary effort between medicine and psychiatry, both in and out of the hos­pital. Because the relapsing, ill ALD patient most often will be admitted to a medical specialist, AUD might not receive enough attention during the medical admission. Psychiatrists can help in initiating AUD treatment in the acute medical setting, which has been shown to improve the out­patient course.⁶ For medically stable ALD patients admitted for inpatient psychiatric care or presenting a clinic, the mental health clinician should be aware of key laboratory and physical exam findings.

Bottom Line
Patients with alcoholic liver disease (ALD) require collaborative care from specialists in addiction, gastroenterology, and psychiatry. Psychiatrists have a role in identifying signs of ALD, prescribing medication to treat alcohol use disorder, and encouraging abstinence. There is some evidence supporting specific medications for varying severity of disease and different phases of recovery. Pharmacotherapy decisions should be made case by case.

Related Resources
• Khan A, Tansel A, White DL, et al. Efficacy of psychosocial interventions in inducing and maintaining alcohol abstinence in patients with chronic liver disease: a systematic review [published online August 6, 2015]. Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2015.07.047.
• Vuittonet CL, Halse M, Leggio L, et al. Pharmacotherapy for alcoholic patients with alcoholic liver disease. Am J Health Syst Pharm. 2014;71(15):1265-1276.

Drug Brand Names
Acamprosate • Campral                       
Baclofen • Lioresal                              
Disulfiram • Antabuse                          
Gabapentin • Neurontin                       
Naltrexone • ReVia, Vivitrol
Pentoxifylline • Trental
Prednisolone • Prelone
Rifaximin • Xifaxan
Topiramate • Topamax

Disclosures
Dr. Winder and Dr. Mellinger report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products. Dr. Fontana receives research funding from Bristol Myers Squibb, Gilead, and Janssen and consults for the Chronic Liver Disease Foundation.

Nightmares are a common feature of posttraumatic stress disorder (PTSD) that could lead to fatigue, impaired concentration, and poor work performance. The α-1 antagonist prazosin decreases noradrenergic hyperactivity and reduces nightmares; however, it can cause adverse effects, be contraindicated, or pro­vide no benefit to some patients. Consider these alternative medications to reduce nightmares in PTSD.

Alpha-2 agonists
Clonidine and guanfacine are α-2 ago­nists, used to treat attention-deficit/hyper­activity disorder and high blood pressure, that decrease noradrenergic activity, and either medication might be preferable to prazosin because they are more likely to cause sedation. A review and a case series showed that many patients—some with comorbid traumatic brain injury—reported fewer nightmares after taking 0.2 to 0.6 mg of clonidine.^1,2 Guanfacine might be more beneficial because it has a longer half-life; 2 mg of guanfacine eliminated nightmares in 1 patient.³ However, in a double-blind placebo-controlled study and an extension study, guanfacine did not reduce night­mares or other PTSD symptoms.^4,5

Initiate 0.1 mg of clonidine at bedtime, and titrate to efficacy or to 0.6 mg. Similarly, initiate guanfacine at 1 mg, and titrate to efficacy or to 4 mg. Monitor for hypoten­sion, excess sedation, dry mouth, and rebound hypertension.

Cyproheptadine
Used to treat serotonin syndrome, cypro­heptadine’s antagonism of serotonin 2A receptors has varying efficacy for reducing nightmares. Some patients have reported a decrease in nightmares at dosages rang­ing from 4 to 24 mg.^1,6 Other studies found no reduction in nightmares or diminished quality of sleep.^1,7

Initiate cyproheptadine at 4 mg/d, titrate every 2 or 3 days, and monitor for sedation, confusion, or reduced efficacy of concurrent serotonergic medications. Cyproheptadine might be preferable for its sedating effect and potential to reduce sexual adverse effects from serotonergic medications.

Topiramate
Topiramate is approved for treatment of epilepsy and migraine headache. At 75 to 100 mg/d in a clinical trial, topira­mate partially or completely suppressed nightmares.⁸ Start with 25 mg/d, titrate to efficacy, and monitor for anorexia, paresthesias, and cognitive impairment. Topiramate might be better than prazosin for patients without renal impairment who want sedation, weight loss, or reduced irritability.

Gabapentin
Gabapentin is approved to treat seizures and postherpetic neuralgia and also is used to treat neuropathic pain. When 300 to 3,600 mg/d (mean dosage, 1,300 mg/d) of gabapentin was added to medication regi­mens, most patients reported decreased fre­quency or intensity of nightmares.⁹ Monitor patients for sedation, dizziness, mood changes, and weight gain. Gabapentin might be an option for patients without renal impairment who have comorbid pain, insomnia, or anxiety.

Are these reasonable alternatives?
Despite small sample sizes in published studies and few randomized trials, cloni­dine, guanfacine, cyproheptadine, topi­ramate, and gabapentin are reasonable alternatives to prazosin for reducing night­mares in patients with PTSD.

Disclosure
The author reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Nightmares are a common feature of posttraumatic stress disorder (PTSD) that could lead to fatigue, impaired concentration, and poor work performance. The α-1 antagonist prazosin decreases noradrenergic hyperactivity and reduces nightmares; however, it can cause adverse effects, be contraindicated, or pro­vide no benefit to some patients. Consider these alternative medications to reduce nightmares in PTSD.

Alpha-2 agonists
Clonidine and guanfacine are α-2 ago­nists, used to treat attention-deficit/hyper­activity disorder and high blood pressure, that decrease noradrenergic activity, and either medication might be preferable to prazosin because they are more likely to cause sedation. A review and a case series showed that many patients—some with comorbid traumatic brain injury—reported fewer nightmares after taking 0.2 to 0.6 mg of clonidine.^1,2 Guanfacine might be more beneficial because it has a longer half-life; 2 mg of guanfacine eliminated nightmares in 1 patient.³ However, in a double-blind placebo-controlled study and an extension study, guanfacine did not reduce night­mares or other PTSD symptoms.^4,5

Initiate 0.1 mg of clonidine at bedtime, and titrate to efficacy or to 0.6 mg. Similarly, initiate guanfacine at 1 mg, and titrate to efficacy or to 4 mg. Monitor for hypoten­sion, excess sedation, dry mouth, and rebound hypertension.

Cyproheptadine
Used to treat serotonin syndrome, cypro­heptadine’s antagonism of serotonin 2A receptors has varying efficacy for reducing nightmares. Some patients have reported a decrease in nightmares at dosages rang­ing from 4 to 24 mg.^1,6 Other studies found no reduction in nightmares or diminished quality of sleep.^1,7

Initiate cyproheptadine at 4 mg/d, titrate every 2 or 3 days, and monitor for sedation, confusion, or reduced efficacy of concurrent serotonergic medications. Cyproheptadine might be preferable for its sedating effect and potential to reduce sexual adverse effects from serotonergic medications.

Topiramate
Topiramate is approved for treatment of epilepsy and migraine headache. At 75 to 100 mg/d in a clinical trial, topira­mate partially or completely suppressed nightmares.⁸ Start with 25 mg/d, titrate to efficacy, and monitor for anorexia, paresthesias, and cognitive impairment. Topiramate might be better than prazosin for patients without renal impairment who want sedation, weight loss, or reduced irritability.

Gabapentin
Gabapentin is approved to treat seizures and postherpetic neuralgia and also is used to treat neuropathic pain. When 300 to 3,600 mg/d (mean dosage, 1,300 mg/d) of gabapentin was added to medication regi­mens, most patients reported decreased fre­quency or intensity of nightmares.⁹ Monitor patients for sedation, dizziness, mood changes, and weight gain. Gabapentin might be an option for patients without renal impairment who have comorbid pain, insomnia, or anxiety.

Are these reasonable alternatives?
Despite small sample sizes in published studies and few randomized trials, cloni­dine, guanfacine, cyproheptadine, topi­ramate, and gabapentin are reasonable alternatives to prazosin for reducing night­mares in patients with PTSD.

Disclosure
The author reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Nightmares are a common feature of posttraumatic stress disorder (PTSD) that could lead to fatigue, impaired concentration, and poor work performance. The α-1 antagonist prazosin decreases noradrenergic hyperactivity and reduces nightmares; however, it can cause adverse effects, be contraindicated, or pro­vide no benefit to some patients. Consider these alternative medications to reduce nightmares in PTSD.

Alpha-2 agonists
Clonidine and guanfacine are α-2 ago­nists, used to treat attention-deficit/hyper­activity disorder and high blood pressure, that decrease noradrenergic activity, and either medication might be preferable to prazosin because they are more likely to cause sedation. A review and a case series showed that many patients—some with comorbid traumatic brain injury—reported fewer nightmares after taking 0.2 to 0.6 mg of clonidine.^1,2 Guanfacine might be more beneficial because it has a longer half-life; 2 mg of guanfacine eliminated nightmares in 1 patient.³ However, in a double-blind placebo-controlled study and an extension study, guanfacine did not reduce night­mares or other PTSD symptoms.^4,5

Initiate 0.1 mg of clonidine at bedtime, and titrate to efficacy or to 0.6 mg. Similarly, initiate guanfacine at 1 mg, and titrate to efficacy or to 4 mg. Monitor for hypoten­sion, excess sedation, dry mouth, and rebound hypertension.

Cyproheptadine
Used to treat serotonin syndrome, cypro­heptadine’s antagonism of serotonin 2A receptors has varying efficacy for reducing nightmares. Some patients have reported a decrease in nightmares at dosages rang­ing from 4 to 24 mg.^1,6 Other studies found no reduction in nightmares or diminished quality of sleep.^1,7

Initiate cyproheptadine at 4 mg/d, titrate every 2 or 3 days, and monitor for sedation, confusion, or reduced efficacy of concurrent serotonergic medications. Cyproheptadine might be preferable for its sedating effect and potential to reduce sexual adverse effects from serotonergic medications.

Topiramate
Topiramate is approved for treatment of epilepsy and migraine headache. At 75 to 100 mg/d in a clinical trial, topira­mate partially or completely suppressed nightmares.⁸ Start with 25 mg/d, titrate to efficacy, and monitor for anorexia, paresthesias, and cognitive impairment. Topiramate might be better than prazosin for patients without renal impairment who want sedation, weight loss, or reduced irritability.

Gabapentin
Gabapentin is approved to treat seizures and postherpetic neuralgia and also is used to treat neuropathic pain. When 300 to 3,600 mg/d (mean dosage, 1,300 mg/d) of gabapentin was added to medication regi­mens, most patients reported decreased fre­quency or intensity of nightmares.⁹ Monitor patients for sedation, dizziness, mood changes, and weight gain. Gabapentin might be an option for patients without renal impairment who have comorbid pain, insomnia, or anxiety.

Are these reasonable alternatives?
Despite small sample sizes in published studies and few randomized trials, cloni­dine, guanfacine, cyproheptadine, topi­ramate, and gabapentin are reasonable alternatives to prazosin for reducing night­mares in patients with PTSD.

Disclosure
The author reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Designer drugs are rapidly making inroads with young people, primar­ily because of easier access, lower overall cost, and nebulous legality. These drugs are made as variants of illicit drugs or new formulations and sold as “research chemicals” and labeled as “not for human consumption,” which allows them to fall outside existing laws. The ingredients typi­cally are not detected in a urine drug screen.

Notoriously addictive, these designer drugs, such as bath salts, are known to incorporate synthetic cathinones—namely, methylone, mephedrone or methylenedioxypyrovalerone (MDPV). The stimu­lant, amphetamine-like effects of bath salts make the drug attractive to adolescents with attention-deficit/hyperactivity disorder (ADHD).

Why do teens gravitate toward bath salts?
Adolescents with undiagnosed ADHD might self-medicate with drugs that are suited for addressing restlessness, intra­psychic turmoil, and other symptoms of ADHD. In 2 case studies, using the self-medication hypothesis, people with ADHD were more likely to seek cocaine by means of “self-selection.”¹ These drug-seeking behaviors often led to cocaine dependence, even when other substances, such as alco­hol or Cannabis, were available.

Methylphenidate and other ADHD phar­macotherapies influence the nucleus accum­bens in a manner similar to that of cocaine. These findings suggest that adolescents with ADHD and cocaine dependence might respond to therapeutic interventions that substitute cocaine with psychostimulants.¹

Bath salts fall within the same spectrum of psychostimulant agents as methylpheni­date and cocaine. MDPV approximates the effect of methylphenidate at low doses, and cocaine at higher doses. It often is marketed under the name “Ivory Wave” and could be confused with cocaine. Self-administration of MDPV can induce psychoactive effects that help alleviate ADHD symptoms; adolescents might continue to experience enhanced concentration and overall per­formance.² Also, because of the low cost of “legal” bath salts, they are an appealing alternative to cocaine for self-medication.

Managing the sequelae of bath salt intoxication
Bath salts may produce sympathomimetic effects greater than cocaine, which require a proactive approach to symptom manage­ment. A medley of unknown ingredients in bath salt preparations makes it difficult for clinicians to gauge the pharmacological impact on individual patients; therefore, therapeutic interventions are on a case-by-case basis. However, emergencies con­cerning amphetamines and amphetamine analogues and derivatives often have simi­lar presentations.

Cardiovascular effects. MDPV-specific urine and blood tests conducted on patients admitted to the emergency room showed a 10-fold increase in overall dopamine levels compared with those who took cocaine. As a sympathomimetic, high doses of dopamine are responsible for raising blood pressure and could lead to the development of pro­nounced cardiovascular effects.^3,4

Agitation. Clinicians generally are advised to treat agitation before providing a more comprehensive assessment of symptoms. Endotracheal intubation often is a required for adequate control of agitation. Bath salt-induced agitation often is treated with IV benzodiazepines.^4,5 Monitor patients for excessive sedation or new-onset “paradoxi­cal agitation” as a function of ongoing benzo-diazepine therapy. Clinicians also may choose to co-administer an antipsychotic with benzodiazepines, although the practice is not uni­versally encouraged for agitation control.

Mephedrone produces a delirious state in conjunction with psychotic symptoms. Antipsychotic therapy has been suggested for addressing ongoing agitation.⁶ 

Tachycardia. Symptomatic treatment of tachycardia involves beta blockers, such as labetalol. Nitroglycerine has evidence of effi­cacy for chest pain associated with cocaine intoxication; however, it is unclear whether it is effective for similar drugs of abuse.⁴

Multi-organ collapse caused by MDPV necessitates aggressive intervention, includ­ing prompt dialysis. Carefully evaluate the patient for the presence of organ-specific insults and initiate supportive measures accordingly. Pronounced agitation with hyperthermia might portend severely com­promised renal, hepatic, and/or cardiac function in MDPV users.⁷ Those who present with MDPV intoxication and concomitant renal injury seem to benefit from hemodi­alysis.⁸ Repeat intoxication events may yield a presentation of acute renal injury replete with metabolic derangements, including metabolic acidosis, hyperuricemia, and rhab­domyolysis.⁹ Thorough patient assessments and interventions are useful in determining long-term outcomes, including issues per­taining to mortality.

Confronting an epidemic
Adolescents are quickly adopting designer drugs as a readily accessible form of recre­ational “legal highs.”¹⁰ Public awareness and educational initiatives can bring to light the dangers of these substances that exert pow­erful and, sometimes, unpredictable psycho­active effects on the user.

Self-mutilation and suicidal ideation also have been documented among those who ingested bath salts. These reports appear to be escalating across Europe and the United States. On a national level, U.S. poison cen­ters have reported an almost 20-fold increase in calls regarding bath salts between 2010 and 2011.⁵ It is of utmost importance for clini­cians and emergency personnel to familiar­ize themselves with the sympathomimetic toxidrome and management for bath salt consumption.

Designer drugs are rapidly making inroads with young people, primar­ily because of easier access, lower overall cost, and nebulous legality. These drugs are made as variants of illicit drugs or new formulations and sold as “research chemicals” and labeled as “not for human consumption,” which allows them to fall outside existing laws. The ingredients typi­cally are not detected in a urine drug screen.

Notoriously addictive, these designer drugs, such as bath salts, are known to incorporate synthetic cathinones—namely, methylone, mephedrone or methylenedioxypyrovalerone (MDPV). The stimu­lant, amphetamine-like effects of bath salts make the drug attractive to adolescents with attention-deficit/hyperactivity disorder (ADHD).

Why do teens gravitate toward bath salts?
Adolescents with undiagnosed ADHD might self-medicate with drugs that are suited for addressing restlessness, intra­psychic turmoil, and other symptoms of ADHD. In 2 case studies, using the self-medication hypothesis, people with ADHD were more likely to seek cocaine by means of “self-selection.”¹ These drug-seeking behaviors often led to cocaine dependence, even when other substances, such as alco­hol or Cannabis, were available.

Methylphenidate and other ADHD phar­macotherapies influence the nucleus accum­bens in a manner similar to that of cocaine. These findings suggest that adolescents with ADHD and cocaine dependence might respond to therapeutic interventions that substitute cocaine with psychostimulants.¹

Bath salts fall within the same spectrum of psychostimulant agents as methylpheni­date and cocaine. MDPV approximates the effect of methylphenidate at low doses, and cocaine at higher doses. It often is marketed under the name “Ivory Wave” and could be confused with cocaine. Self-administration of MDPV can induce psychoactive effects that help alleviate ADHD symptoms; adolescents might continue to experience enhanced concentration and overall per­formance.² Also, because of the low cost of “legal” bath salts, they are an appealing alternative to cocaine for self-medication.

Managing the sequelae of bath salt intoxication
Bath salts may produce sympathomimetic effects greater than cocaine, which require a proactive approach to symptom manage­ment. A medley of unknown ingredients in bath salt preparations makes it difficult for clinicians to gauge the pharmacological impact on individual patients; therefore, therapeutic interventions are on a case-by-case basis. However, emergencies con­cerning amphetamines and amphetamine analogues and derivatives often have simi­lar presentations.

Cardiovascular effects. MDPV-specific urine and blood tests conducted on patients admitted to the emergency room showed a 10-fold increase in overall dopamine levels compared with those who took cocaine. As a sympathomimetic, high doses of dopamine are responsible for raising blood pressure and could lead to the development of pro­nounced cardiovascular effects.^3,4

Agitation. Clinicians generally are advised to treat agitation before providing a more comprehensive assessment of symptoms. Endotracheal intubation often is a required for adequate control of agitation. Bath salt-induced agitation often is treated with IV benzodiazepines.^4,5 Monitor patients for excessive sedation or new-onset “paradoxi­cal agitation” as a function of ongoing benzo-diazepine therapy. Clinicians also may choose to co-administer an antipsychotic with benzodiazepines, although the practice is not uni­versally encouraged for agitation control.

Mephedrone produces a delirious state in conjunction with psychotic symptoms. Antipsychotic therapy has been suggested for addressing ongoing agitation.⁶ 

Tachycardia. Symptomatic treatment of tachycardia involves beta blockers, such as labetalol. Nitroglycerine has evidence of effi­cacy for chest pain associated with cocaine intoxication; however, it is unclear whether it is effective for similar drugs of abuse.⁴

Multi-organ collapse caused by MDPV necessitates aggressive intervention, includ­ing prompt dialysis. Carefully evaluate the patient for the presence of organ-specific insults and initiate supportive measures accordingly. Pronounced agitation with hyperthermia might portend severely com­promised renal, hepatic, and/or cardiac function in MDPV users.⁷ Those who present with MDPV intoxication and concomitant renal injury seem to benefit from hemodi­alysis.⁸ Repeat intoxication events may yield a presentation of acute renal injury replete with metabolic derangements, including metabolic acidosis, hyperuricemia, and rhab­domyolysis.⁹ Thorough patient assessments and interventions are useful in determining long-term outcomes, including issues per­taining to mortality.

Confronting an epidemic
Adolescents are quickly adopting designer drugs as a readily accessible form of recre­ational “legal highs.”¹⁰ Public awareness and educational initiatives can bring to light the dangers of these substances that exert pow­erful and, sometimes, unpredictable psycho­active effects on the user.

Self-mutilation and suicidal ideation also have been documented among those who ingested bath salts. These reports appear to be escalating across Europe and the United States. On a national level, U.S. poison cen­ters have reported an almost 20-fold increase in calls regarding bath salts between 2010 and 2011.⁵ It is of utmost importance for clini­cians and emergency personnel to familiar­ize themselves with the sympathomimetic toxidrome and management for bath salt consumption.

Designer drugs are rapidly making inroads with young people, primar­ily because of easier access, lower overall cost, and nebulous legality. These drugs are made as variants of illicit drugs or new formulations and sold as “research chemicals” and labeled as “not for human consumption,” which allows them to fall outside existing laws. The ingredients typi­cally are not detected in a urine drug screen.

Notoriously addictive, these designer drugs, such as bath salts, are known to incorporate synthetic cathinones—namely, methylone, mephedrone or methylenedioxypyrovalerone (MDPV). The stimu­lant, amphetamine-like effects of bath salts make the drug attractive to adolescents with attention-deficit/hyperactivity disorder (ADHD).

Why do teens gravitate toward bath salts?
Adolescents with undiagnosed ADHD might self-medicate with drugs that are suited for addressing restlessness, intra­psychic turmoil, and other symptoms of ADHD. In 2 case studies, using the self-medication hypothesis, people with ADHD were more likely to seek cocaine by means of “self-selection.”¹ These drug-seeking behaviors often led to cocaine dependence, even when other substances, such as alco­hol or Cannabis, were available.

Methylphenidate and other ADHD phar­macotherapies influence the nucleus accum­bens in a manner similar to that of cocaine. These findings suggest that adolescents with ADHD and cocaine dependence might respond to therapeutic interventions that substitute cocaine with psychostimulants.¹

Bath salts fall within the same spectrum of psychostimulant agents as methylpheni­date and cocaine. MDPV approximates the effect of methylphenidate at low doses, and cocaine at higher doses. It often is marketed under the name “Ivory Wave” and could be confused with cocaine. Self-administration of MDPV can induce psychoactive effects that help alleviate ADHD symptoms; adolescents might continue to experience enhanced concentration and overall per­formance.² Also, because of the low cost of “legal” bath salts, they are an appealing alternative to cocaine for self-medication.

Managing the sequelae of bath salt intoxication
Bath salts may produce sympathomimetic effects greater than cocaine, which require a proactive approach to symptom manage­ment. A medley of unknown ingredients in bath salt preparations makes it difficult for clinicians to gauge the pharmacological impact on individual patients; therefore, therapeutic interventions are on a case-by-case basis. However, emergencies con­cerning amphetamines and amphetamine analogues and derivatives often have simi­lar presentations.

Cardiovascular effects. MDPV-specific urine and blood tests conducted on patients admitted to the emergency room showed a 10-fold increase in overall dopamine levels compared with those who took cocaine. As a sympathomimetic, high doses of dopamine are responsible for raising blood pressure and could lead to the development of pro­nounced cardiovascular effects.^3,4

Agitation. Clinicians generally are advised to treat agitation before providing a more comprehensive assessment of symptoms. Endotracheal intubation often is a required for adequate control of agitation. Bath salt-induced agitation often is treated with IV benzodiazepines.^4,5 Monitor patients for excessive sedation or new-onset “paradoxi­cal agitation” as a function of ongoing benzo-diazepine therapy. Clinicians also may choose to co-administer an antipsychotic with benzodiazepines, although the practice is not uni­versally encouraged for agitation control.

Mephedrone produces a delirious state in conjunction with psychotic symptoms. Antipsychotic therapy has been suggested for addressing ongoing agitation.⁶ 

Tachycardia. Symptomatic treatment of tachycardia involves beta blockers, such as labetalol. Nitroglycerine has evidence of effi­cacy for chest pain associated with cocaine intoxication; however, it is unclear whether it is effective for similar drugs of abuse.⁴

Multi-organ collapse caused by MDPV necessitates aggressive intervention, includ­ing prompt dialysis. Carefully evaluate the patient for the presence of organ-specific insults and initiate supportive measures accordingly. Pronounced agitation with hyperthermia might portend severely com­promised renal, hepatic, and/or cardiac function in MDPV users.⁷ Those who present with MDPV intoxication and concomitant renal injury seem to benefit from hemodi­alysis.⁸ Repeat intoxication events may yield a presentation of acute renal injury replete with metabolic derangements, including metabolic acidosis, hyperuricemia, and rhab­domyolysis.⁹ Thorough patient assessments and interventions are useful in determining long-term outcomes, including issues per­taining to mortality.

Confronting an epidemic
Adolescents are quickly adopting designer drugs as a readily accessible form of recre­ational “legal highs.”¹⁰ Public awareness and educational initiatives can bring to light the dangers of these substances that exert pow­erful and, sometimes, unpredictable psycho­active effects on the user.

Self-mutilation and suicidal ideation also have been documented among those who ingested bath salts. These reports appear to be escalating across Europe and the United States. On a national level, U.S. poison cen­ters have reported an almost 20-fold increase in calls regarding bath salts between 2010 and 2011.⁵ It is of utmost importance for clini­cians and emergency personnel to familiar­ize themselves with the sympathomimetic toxidrome and management for bath salt consumption.

Few methods can build your practice and reputation as well as blogging— nor can they give you as much grief. Your opinions can become known to a wide audience; you might influence public think­ing or behavior; and you might become associated with a particular expertise at almost no financial cost. Yet, having regular deadlines to produce creative content can be stressful, and the time required to do it well has its own cost.

What is it?
“Blog” is the collapsed expression of “Web log.” Blogging is posting your thoughts on a Web site for colleagues or consumers, or both, to read. Typically, a blog is written as if you were writing a newspaper column; word count varies, from 250 to 1,000 words. Alternative formats are auditory (podcasts) or visual (vlog) but those media require greater technical proficiency and take more time to produce.

Whether you decide to write or record your blog entry, be guided by this advice:
   • The subject matter can be anything you choose, but will be easiest to write when what you write about is based on your expertise.
   • The format can be stream of consciousness,essay, or bulleted lists or slides; the latter is the most common and often follows a how-to or list format (eg, “Top [number] strategies to XYZ” or “[Number] of things you didn’t know about ABC”).
   • End the blog with a cliffhanger or a call-to-action statement that invites readers to comment (especially if you then comment on their comments), to help drive interest.
   • Generate material at a consistent interval (eg, once a week or twice a month), so your readers can look forward to your soliloquies on a regular basis.

Your professional Web site can serve as a venue for your blog. Using a WordPress^a-based site, for example, offers a user-friendly way to compose your dispatch, add format­ting (headers, bullets, color, images, etc.) as you see fit, and then publish it. It requires little technical expertise and adds no extra expense to your Web site. Alternatively, you might wish to contact editors at magazines or blog aggregators with story ideas, and let them handle the logistics if your content is appealing to them.

^aWordPress is a Web site creation and management tool.

Spreading the word
There is much you can do to publicize your blog.
   • Take advantage of social media. Build up your contacts on LinkedIn and follow other bloggers and large news sites on Twitter. Often, recipients will respond in-kind. Then, for each new piece, post or tweet it in these accounts.
   • Offer an e-mail subscription so that readers can easily follow you (by means of a free WordPress plug-in, for example).
   • Be found in search engines, such as Google, by writing high-quality, original content. Don’t force certain keywords into your article in the hopes that search engines find them—doing so tends to make writing more robotic and can lower your page rank.

Successful strategies
Regularly setting time aside so that the process is enjoyable and not onerously deadline-driven lends satisfaction to the experience and comes through in the quality of the composition. To save time, consider dictating your thoughts to your computer or phone, then outsource transcription.

Don’t overlook the bounty of material in your day-to-day life: stories from sessions; discoveries from your own reading or the latest news; and lectures you give. All of these can serve as inspiration and mate­rial for posts. Jot down these moments in a notebook as soon as they come up, or else the memory will likely slip away.

Just as with other forms of social media, be mindful of appropriate boundaries. Do not disclose identifying patient infor­mation; even revealing facets of your life might not be appropriate for current or future patients to have access to. On the other hand, it might be therapeutic for them to know select personal information, such as how you have handled past dilem­mas, that reveals you are a real person (a “whole object” in psychoanalytic terms), and that models meaningful thoughts or deeds.

You’ll find your voice, in time
Getting started with blogging often is the toughest part. Finding the right for­mat, material, and routine will take time. Eventually, you will find your blogging voice, and will value the unique opportu­nity to brand your practice and yourself, provide valuable content to your readers, and find an outlet for artistic expression.

Disclosure
Dr. Braslow is the founder of Luminello.com.

Few methods can build your practice and reputation as well as blogging— nor can they give you as much grief. Your opinions can become known to a wide audience; you might influence public think­ing or behavior; and you might become associated with a particular expertise at almost no financial cost. Yet, having regular deadlines to produce creative content can be stressful, and the time required to do it well has its own cost.

What is it?
“Blog” is the collapsed expression of “Web log.” Blogging is posting your thoughts on a Web site for colleagues or consumers, or both, to read. Typically, a blog is written as if you were writing a newspaper column; word count varies, from 250 to 1,000 words. Alternative formats are auditory (podcasts) or visual (vlog) but those media require greater technical proficiency and take more time to produce.

Whether you decide to write or record your blog entry, be guided by this advice:
   • The subject matter can be anything you choose, but will be easiest to write when what you write about is based on your expertise.
   • The format can be stream of consciousness,essay, or bulleted lists or slides; the latter is the most common and often follows a how-to or list format (eg, “Top [number] strategies to XYZ” or “[Number] of things you didn’t know about ABC”).
   • End the blog with a cliffhanger or a call-to-action statement that invites readers to comment (especially if you then comment on their comments), to help drive interest.
   • Generate material at a consistent interval (eg, once a week or twice a month), so your readers can look forward to your soliloquies on a regular basis.

Your professional Web site can serve as a venue for your blog. Using a WordPress^a-based site, for example, offers a user-friendly way to compose your dispatch, add format­ting (headers, bullets, color, images, etc.) as you see fit, and then publish it. It requires little technical expertise and adds no extra expense to your Web site. Alternatively, you might wish to contact editors at magazines or blog aggregators with story ideas, and let them handle the logistics if your content is appealing to them.

^aWordPress is a Web site creation and management tool.

Spreading the word
There is much you can do to publicize your blog.
   • Take advantage of social media. Build up your contacts on LinkedIn and follow other bloggers and large news sites on Twitter. Often, recipients will respond in-kind. Then, for each new piece, post or tweet it in these accounts.
   • Offer an e-mail subscription so that readers can easily follow you (by means of a free WordPress plug-in, for example).
   • Be found in search engines, such as Google, by writing high-quality, original content. Don’t force certain keywords into your article in the hopes that search engines find them—doing so tends to make writing more robotic and can lower your page rank.

Successful strategies
Regularly setting time aside so that the process is enjoyable and not onerously deadline-driven lends satisfaction to the experience and comes through in the quality of the composition. To save time, consider dictating your thoughts to your computer or phone, then outsource transcription.

Don’t overlook the bounty of material in your day-to-day life: stories from sessions; discoveries from your own reading or the latest news; and lectures you give. All of these can serve as inspiration and mate­rial for posts. Jot down these moments in a notebook as soon as they come up, or else the memory will likely slip away.

Just as with other forms of social media, be mindful of appropriate boundaries. Do not disclose identifying patient infor­mation; even revealing facets of your life might not be appropriate for current or future patients to have access to. On the other hand, it might be therapeutic for them to know select personal information, such as how you have handled past dilem­mas, that reveals you are a real person (a “whole object” in psychoanalytic terms), and that models meaningful thoughts or deeds.

You’ll find your voice, in time
Getting started with blogging often is the toughest part. Finding the right for­mat, material, and routine will take time. Eventually, you will find your blogging voice, and will value the unique opportu­nity to brand your practice and yourself, provide valuable content to your readers, and find an outlet for artistic expression.

Disclosure
Dr. Braslow is the founder of Luminello.com.

Few methods can build your practice and reputation as well as blogging— nor can they give you as much grief. Your opinions can become known to a wide audience; you might influence public think­ing or behavior; and you might become associated with a particular expertise at almost no financial cost. Yet, having regular deadlines to produce creative content can be stressful, and the time required to do it well has its own cost.

What is it?
“Blog” is the collapsed expression of “Web log.” Blogging is posting your thoughts on a Web site for colleagues or consumers, or both, to read. Typically, a blog is written as if you were writing a newspaper column; word count varies, from 250 to 1,000 words. Alternative formats are auditory (podcasts) or visual (vlog) but those media require greater technical proficiency and take more time to produce.

Whether you decide to write or record your blog entry, be guided by this advice:
   • The subject matter can be anything you choose, but will be easiest to write when what you write about is based on your expertise.
   • The format can be stream of consciousness,essay, or bulleted lists or slides; the latter is the most common and often follows a how-to or list format (eg, “Top [number] strategies to XYZ” or “[Number] of things you didn’t know about ABC”).
   • End the blog with a cliffhanger or a call-to-action statement that invites readers to comment (especially if you then comment on their comments), to help drive interest.
   • Generate material at a consistent interval (eg, once a week or twice a month), so your readers can look forward to your soliloquies on a regular basis.

Your professional Web site can serve as a venue for your blog. Using a WordPress^a-based site, for example, offers a user-friendly way to compose your dispatch, add format­ting (headers, bullets, color, images, etc.) as you see fit, and then publish it. It requires little technical expertise and adds no extra expense to your Web site. Alternatively, you might wish to contact editors at magazines or blog aggregators with story ideas, and let them handle the logistics if your content is appealing to them.

^aWordPress is a Web site creation and management tool.

Spreading the word
There is much you can do to publicize your blog.
   • Take advantage of social media. Build up your contacts on LinkedIn and follow other bloggers and large news sites on Twitter. Often, recipients will respond in-kind. Then, for each new piece, post or tweet it in these accounts.
   • Offer an e-mail subscription so that readers can easily follow you (by means of a free WordPress plug-in, for example).
   • Be found in search engines, such as Google, by writing high-quality, original content. Don’t force certain keywords into your article in the hopes that search engines find them—doing so tends to make writing more robotic and can lower your page rank.

Successful strategies
Regularly setting time aside so that the process is enjoyable and not onerously deadline-driven lends satisfaction to the experience and comes through in the quality of the composition. To save time, consider dictating your thoughts to your computer or phone, then outsource transcription.

Don’t overlook the bounty of material in your day-to-day life: stories from sessions; discoveries from your own reading or the latest news; and lectures you give. All of these can serve as inspiration and mate­rial for posts. Jot down these moments in a notebook as soon as they come up, or else the memory will likely slip away.

Just as with other forms of social media, be mindful of appropriate boundaries. Do not disclose identifying patient infor­mation; even revealing facets of your life might not be appropriate for current or future patients to have access to. On the other hand, it might be therapeutic for them to know select personal information, such as how you have handled past dilem­mas, that reveals you are a real person (a “whole object” in psychoanalytic terms), and that models meaningful thoughts or deeds.

You’ll find your voice, in time
Getting started with blogging often is the toughest part. Finding the right for­mat, material, and routine will take time. Eventually, you will find your blogging voice, and will value the unique opportu­nity to brand your practice and yourself, provide valuable content to your readers, and find an outlet for artistic expression.

Disclosure
Dr. Braslow is the founder of Luminello.com.

When a patient who has a preexisting medical illness seeks prenatal care, the obstetrician asks herself (himself) 2 questions:
   • What impact will the illness have on the pregnancy?
   • What impact will the pregnancy have on the illness?

Depression is both a pregnancy-associated and pregnancy­-independent illness, which, in the setting of a pregnant woman who has a depressive disorder, makes these questions particu­larly difficult to answer. In such a case, coordination of care with a mental health provider is essential.

Awareness of the obstetrical complications associated with depression during pregnancy, as well as their implications for the future health of the mother–infant dyad, is important for the entire care team. This article reviews the associations and interconnectedness of depression with complications of preg­nancy, childbirth, and the neonatal period.

Diagnosis of depression during prenatal care
The American College of Obstetricians and Gynecologists (ACOG) states that evidence is insufficient to support a rec­ommendation for universal screening for depression among prenatal patients, although such screening should be considered.¹ There is considerable variability among obstetrical pro­viders regarding the practice of depression screening; tools to be used if such screening is done; and screening frequency through the pregnancy.

Discernment of depression is difficult. Many somatic symptoms of depression overlap with common prenatal complaints and, consequentially, can be overlooked. Among a sample of 700 pregnant women, for example, 56% complained of lack of energy; 19%, of insomnia; and 19%, of appe­tite changes.² Weight change, of course, is universal.

The 10-question self-rating Edinburgh Postnatal Depression Scale has been vali­dated for use during pregnancy and post­natally. This screening instrument can be helpful for differentiating purely physical complaints from mental distress due to depressive symptoms.^2,3

When an obstetrical provider suspects a depressive disorder, or one has been diagnosed, she (he) faces the problem of what to do with that information. Women of low socioeconomic status and victims of domestic violence are at increased risk of depression during pregnancy, but barri­ers to appropriate referral can seem nearly insurmountable because they lack insur­ance and social support.^4-9

In addition, within the setting of numer­ous tasks that need attending during the relatively short prenatal period, it is com­mon for women newly given a diagnosis of depression to fail to follow up on a refer­ral to a mental health provider.

Although most providers will “check in” with a depressed or at-risk patient at each prenatal visit about her mood, any effort at follow-up can be overshadowed by tangible physical concerns, such as pre­term contractions, fetal growth restriction, and coordination of routine testing that has been delayed because of scant prena­tal care. All these physical concerns and circumstances of care are associated with maternal depression, as we will discuss.

Preterm labor and birth
Preterm labor is defined as uterine contrac­tions that lead to cervical change before 37 weeks gestational age. Preterm labor increases the risk of preterm birth; pre­term labor precedes 50% of preterm births. Preterm birth is the leading cause of neona­tal mortality in the United States, and rates of morbidity and mortality increase as ges­tational age decreases.¹⁰ Common neonatal complications related to prematurity are shown in the Figure.¹¹

Women who suffer from depression have an increased risk of preterm labor and preterm birth, as many studies of treated and untreated depressed pregnant women have shown.^12-20 The causative mechanism is unknown; it has been proposed that the increase in maternal cortisol production asso­ciated with depression and distress triggers overproduction of placental cortisol releasing hormone, which is thought to be involved in initiation of parturition.^21,22 Depression also is associated with other risk factors for preterm birth, such as low socioeconomic status, sub­stance use, and smoking.

Intrauterine growth restriction
Women who have depression during preg­nancy have an increased risk of intrauterine growth restriction (IUGR), which leads to delivery of an infant who is small for ges­tational age (SGA) or of low birth weight (LBW) (weighing <2,500 g at birth), or both.²³ Again, the basis of the association between depression and IUGR and SGA is unknown; it is theorized that increased levels of cortisol and catecholamines associated with maternal distress might, by increasing blood pressure and inducing vasoconstriction, cause placen­tal hypoperfusion.^24,25

It also is possible that the association of depression with other risk factors for IUGR, such as smoking, substance use, obesity, and poor prenatal care, puts the infants of depressed women at risk of growth restric­tion.²⁶ Several large-scale studies showed that the association between LBW and depres­sion is lost when smoking and substance use are accounted for; other studies, however, found a persistent association in untreated depressed women when smokers, substance users, and drinkers were excluded.^17,26,27

IUGR infants are at increased risk of iat­rogenic prematurity and stillbirth. Fetuses that weigh <10th percentile for their ges­tational age are delivered no later than 40 weeks; delivery can be indicated as early as 32 weeks, depending on the results of other antenatal tests. Women who have a growth-restricted infant have a higher risk of cesarean delivery because growth-restricted infants often have less reserve and poorer tolerance of labor.

Preeclampsia and eclampsia
Preeclampsia is defined as blood pressure >140/90 mm HG on at least 2 occasions, with proteinuria, that occurs later than the twentieth week of pregnancy in women who did not have hypertension or renal dysfunction at baseline. Preeclampsia is a progressive disease that can cause severe maternal morbidity, including renal failure, stroke, hepatic rupture, pulmonary edema, and heart failure.

Eclampsia refers to onset of seizures in the setting of preeclampsia. These 2 hyperten­sive disorders are the third leading world wide cause of maternal mortality.²⁸

Depressed women have an elevated risk of preeclampsia. The association between preeclampsia and depression might be caused by the presence of increased levels of inflammatory mediators^29,30; other comorbidities, such as increased body mass index, also might be involved, but the risk for preeclampsia in depressed women still is increased after controlling for obesity.³¹

The presence of preeclampsia is respon­sible for a high percentage of iatrogenic pre­term births, because the cure for the disorder is delivery—even at early or previable gesta­tional age. Complication rates for mother and infant are high.

The presence of preeclampsia is a sig­nificant risk factor for intrauterine fetal demise. Treating the mother after delivery involves administration of IV magnesium for 24 hours; often, the mother is separated from her infant for a day after birth.

Impact on prenatal care
Depression increases odds that women will have fewer prenatal visits.³² During pregnancy, women typically initiate pre­natal care during the first trimester, when pregnancy-dating ultrasonography and early screening tests for chromosomal abnormalities are performed. Prenatal vis­its occur monthly until the third trimes­ter, then every 2 weeks between 32 and 36 weeks’ gestation, increasing to weekly after 36 weeks’ gestation.

The increased number of visits in late pregnancy allows for early detection and treatment of hypertensive disorders; assesses fetal well-being; and decreases the risks of morbidity and mortality for mother and fetus.³³ Because women who suffer from depression are at increased risk of an array of adverse pregnancy outcomes, the impor­tance of regular and timely prenatal care cannot be understated.

In addition, the prenatal visit gives the obstetrician the opportunity to connect women with other specialists for manage­ment of any unmet medical needs. One study showed that, when women have adequate prenatal care (measured by the number of visits), the association between preterm birth and self-reported maternal depression was eliminated.³⁴

Substance use
Substance use and depression often co-exist.^35,36 Unlike screening for depression, screening for substance use is universal dur­ing prenatal care. Studies have shown that women who screen positive for depression are at higher risk of a number of comorbidi­ties, including substance use.^37,38 Conversely, women who use substances are more likely to screen positive for depression.

Evidence suggests that best practice might be to screen for depression in any woman who has a positive drug screen, if a provider is not routinely screening their general patient population.³⁹ Substance use in pregnancy is associated with a number of poor outcomes, including placental abrup­tion (cocaine use); dysmorphic facies and congenital anomalies (alcohol); and neonatal abstinence syndrome (heroin).

Antidepressants in pregnancy
A full discussion of the risks and ben­efits associated with pharmacotherapy for depression in pregnancy is beyond the scope of this article. Generally, antidepressant use is fraught with concerns over teratogenic­ity and adverse fetal outcomes. Although ACOG states that (1) pharmacotherapy for depression should be individualized and (2) most selective serotonin reuptake inhibi­tors (SSRIs) are not considered major terato­genic agents, many obstetricians and patients feel uncomfortable using these medications in pregnancy.⁴⁰ Often, pre-pregnancy antide­pressants are discontinued in the first trimes­ter; one large population-based study found that only 0.9% of women who had depres­sion filled their antidepressant prescription consistently throughout their pregnancy.⁴¹

It is unclear whether antidepressant use in pregnancy contributes to the risk of preterm birth seen in women who have depression. In a large population-based study, use of antidepressants in the second trimester was associated with preterm delivery but severe depression was not.¹⁸ A recent meta-analysis revealed an increased risk of preterm birth in women who used an antidepressant, com­pared with healthy women and untreated depressed women.⁴²

Research limits, unanswered questions. Regrettably, it is difficult to untangle risk factors for preterm birth among depressed women without randomized controlled studies that are not ethically feasible. It can­not be said with certainty whether antide­pressant pharmacotherapy is associated with a higher risk of preterm birth than depression alone.

Likewise, it is difficult to clarify the extent to which antidepressants contribute to infant growth restriction, if at all. Two recent meta-analyses concluded that exposure to antidepressants is associated with a statisti­cally significant risk of LBW.^42,43 However, increased severity of depressive symptoms generally is associated with exposure to anti­depressants during pregnancy, and a ran­domized controlled trial is, again, impossible to conduct for ethical reasons.

Whereas a plausible biological mecha­nism associating IUGR, SGA, and LBW with depression exists, the same cannot be said for antidepressants. In one study, exposure to maternal depression altered the expres­sion of certain placental genes but exposure to SSRIs did not cause further changes. This suggests that, on a cellular level, placental function might differ in depressed women.⁴⁴ Although antidepressants do cross the pla­centa, it remains to be seen whether fetal growth is impacted as a result. One study found decreased fetal head circumference in infants who had been exposed to antidepres­sants during pregnancy, but no increased risk for having a SGA or LWB infant.⁴⁵

Obstetrical management and mental health implications
Treated or not, women who suffer depres­sion are a high-risk group when it comes to preterm birth and a host of other pregnancy comorbidities. Women with serious compli­cations of pregnancy often are hospitalized for observation, and can undergo a pro­longed stay when close proximity to medical services or a surgical suite is required.

For example, hospitalization until deliv­ery is the standard of care for women who have preterm premature rupture of mem­branes or preeclampsia before 34 weeks’ gestation. Prolonged inpatient admis­sions and associated restriction of activity is profoundly deleterious on mood, with depression and anxiety significantly cor­related with length of stay.^46,47 Given the associations between depression and pre­term birth, it might be reasonable to con­sider screening antenatal inpatients at risk of preterm birth for depression on a regu­lar basis, so that treatment can be initiated if needed.

Depression during pregnancy is rela­tively common; an estimated 12.7% of pregnant women are affected at some time between conception and birth.⁴⁸ Not only does depression appear to have deleterious effects on pregnancy outcomes, it also plays a pivotal role in the qualitative experience of pregnancy for the mother.

Bottom Line
Awareness of obstetrical complications associated with depression in pregnancy is important for the entire care team, including the psychiatrist and obstetrician. Depression not only appears to have deleterious effects on pregnancy outcomes, it also plays a pivotal role in the qualitative experience of pregnancy for the mother. Antidepressant use generally is fraught with concerns over teratogenicity and adverse fetal outcomes.

Related Resources
• Freeman MP. Some SSRIs are better than others for pregnant women (audio interview). Current Psychiatry. 2014;13(7). http://www.currentpsychiatry.com/specialty-focus/practice-trends/article/some-ssris-are-better-thanothers-for-pregnant-women/e3adb4704e25492f3e15331fc1cc058d.html.
• Freeman MP, Joffe H, Cohen LS. Postpartum depression: Help patients find the right treatment. Current Psychiatry. 2012;11(11):14-16,19-21.

Disclosures
Dr. Habecker reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Freeman is a member of the advisory board of JDS Therapeutics, Sunovion Pharmaceuticals, Inc., and Takeda Pharmaceutical Co. She receives research grant support from Takeda Pharmaceutical Co.

When a patient who has a preexisting medical illness seeks prenatal care, the obstetrician asks herself (himself) 2 questions:
   • What impact will the illness have on the pregnancy?
   • What impact will the pregnancy have on the illness?

Depression is both a pregnancy-associated and pregnancy­-independent illness, which, in the setting of a pregnant woman who has a depressive disorder, makes these questions particu­larly difficult to answer. In such a case, coordination of care with a mental health provider is essential.

Awareness of the obstetrical complications associated with depression during pregnancy, as well as their implications for the future health of the mother–infant dyad, is important for the entire care team. This article reviews the associations and interconnectedness of depression with complications of preg­nancy, childbirth, and the neonatal period.

Diagnosis of depression during prenatal care
The American College of Obstetricians and Gynecologists (ACOG) states that evidence is insufficient to support a rec­ommendation for universal screening for depression among prenatal patients, although such screening should be considered.¹ There is considerable variability among obstetrical pro­viders regarding the practice of depression screening; tools to be used if such screening is done; and screening frequency through the pregnancy.

Discernment of depression is difficult. Many somatic symptoms of depression overlap with common prenatal complaints and, consequentially, can be overlooked. Among a sample of 700 pregnant women, for example, 56% complained of lack of energy; 19%, of insomnia; and 19%, of appe­tite changes.² Weight change, of course, is universal.

The 10-question self-rating Edinburgh Postnatal Depression Scale has been vali­dated for use during pregnancy and post­natally. This screening instrument can be helpful for differentiating purely physical complaints from mental distress due to depressive symptoms.^2,3

When an obstetrical provider suspects a depressive disorder, or one has been diagnosed, she (he) faces the problem of what to do with that information. Women of low socioeconomic status and victims of domestic violence are at increased risk of depression during pregnancy, but barri­ers to appropriate referral can seem nearly insurmountable because they lack insur­ance and social support.^4-9

In addition, within the setting of numer­ous tasks that need attending during the relatively short prenatal period, it is com­mon for women newly given a diagnosis of depression to fail to follow up on a refer­ral to a mental health provider.

Although most providers will “check in” with a depressed or at-risk patient at each prenatal visit about her mood, any effort at follow-up can be overshadowed by tangible physical concerns, such as pre­term contractions, fetal growth restriction, and coordination of routine testing that has been delayed because of scant prena­tal care. All these physical concerns and circumstances of care are associated with maternal depression, as we will discuss.

Preterm labor and birth
Preterm labor is defined as uterine contrac­tions that lead to cervical change before 37 weeks gestational age. Preterm labor increases the risk of preterm birth; pre­term labor precedes 50% of preterm births. Preterm birth is the leading cause of neona­tal mortality in the United States, and rates of morbidity and mortality increase as ges­tational age decreases.¹⁰ Common neonatal complications related to prematurity are shown in the Figure.¹¹

Women who suffer from depression have an increased risk of preterm labor and preterm birth, as many studies of treated and untreated depressed pregnant women have shown.^12-20 The causative mechanism is unknown; it has been proposed that the increase in maternal cortisol production asso­ciated with depression and distress triggers overproduction of placental cortisol releasing hormone, which is thought to be involved in initiation of parturition.^21,22 Depression also is associated with other risk factors for preterm birth, such as low socioeconomic status, sub­stance use, and smoking.

Intrauterine growth restriction
Women who have depression during preg­nancy have an increased risk of intrauterine growth restriction (IUGR), which leads to delivery of an infant who is small for ges­tational age (SGA) or of low birth weight (LBW) (weighing <2,500 g at birth), or both.²³ Again, the basis of the association between depression and IUGR and SGA is unknown; it is theorized that increased levels of cortisol and catecholamines associated with maternal distress might, by increasing blood pressure and inducing vasoconstriction, cause placen­tal hypoperfusion.^24,25

It also is possible that the association of depression with other risk factors for IUGR, such as smoking, substance use, obesity, and poor prenatal care, puts the infants of depressed women at risk of growth restric­tion.²⁶ Several large-scale studies showed that the association between LBW and depres­sion is lost when smoking and substance use are accounted for; other studies, however, found a persistent association in untreated depressed women when smokers, substance users, and drinkers were excluded.^17,26,27

IUGR infants are at increased risk of iat­rogenic prematurity and stillbirth. Fetuses that weigh <10th percentile for their ges­tational age are delivered no later than 40 weeks; delivery can be indicated as early as 32 weeks, depending on the results of other antenatal tests. Women who have a growth-restricted infant have a higher risk of cesarean delivery because growth-restricted infants often have less reserve and poorer tolerance of labor.

Preeclampsia and eclampsia
Preeclampsia is defined as blood pressure >140/90 mm HG on at least 2 occasions, with proteinuria, that occurs later than the twentieth week of pregnancy in women who did not have hypertension or renal dysfunction at baseline. Preeclampsia is a progressive disease that can cause severe maternal morbidity, including renal failure, stroke, hepatic rupture, pulmonary edema, and heart failure.

Eclampsia refers to onset of seizures in the setting of preeclampsia. These 2 hyperten­sive disorders are the third leading world wide cause of maternal mortality.²⁸

Depressed women have an elevated risk of preeclampsia. The association between preeclampsia and depression might be caused by the presence of increased levels of inflammatory mediators^29,30; other comorbidities, such as increased body mass index, also might be involved, but the risk for preeclampsia in depressed women still is increased after controlling for obesity.³¹

The presence of preeclampsia is respon­sible for a high percentage of iatrogenic pre­term births, because the cure for the disorder is delivery—even at early or previable gesta­tional age. Complication rates for mother and infant are high.

The presence of preeclampsia is a sig­nificant risk factor for intrauterine fetal demise. Treating the mother after delivery involves administration of IV magnesium for 24 hours; often, the mother is separated from her infant for a day after birth.

Impact on prenatal care
Depression increases odds that women will have fewer prenatal visits.³² During pregnancy, women typically initiate pre­natal care during the first trimester, when pregnancy-dating ultrasonography and early screening tests for chromosomal abnormalities are performed. Prenatal vis­its occur monthly until the third trimes­ter, then every 2 weeks between 32 and 36 weeks’ gestation, increasing to weekly after 36 weeks’ gestation.

The increased number of visits in late pregnancy allows for early detection and treatment of hypertensive disorders; assesses fetal well-being; and decreases the risks of morbidity and mortality for mother and fetus.³³ Because women who suffer from depression are at increased risk of an array of adverse pregnancy outcomes, the impor­tance of regular and timely prenatal care cannot be understated.

In addition, the prenatal visit gives the obstetrician the opportunity to connect women with other specialists for manage­ment of any unmet medical needs. One study showed that, when women have adequate prenatal care (measured by the number of visits), the association between preterm birth and self-reported maternal depression was eliminated.³⁴

Substance use
Substance use and depression often co-exist.^35,36 Unlike screening for depression, screening for substance use is universal dur­ing prenatal care. Studies have shown that women who screen positive for depression are at higher risk of a number of comorbidi­ties, including substance use.^37,38 Conversely, women who use substances are more likely to screen positive for depression.

Evidence suggests that best practice might be to screen for depression in any woman who has a positive drug screen, if a provider is not routinely screening their general patient population.³⁹ Substance use in pregnancy is associated with a number of poor outcomes, including placental abrup­tion (cocaine use); dysmorphic facies and congenital anomalies (alcohol); and neonatal abstinence syndrome (heroin).

Antidepressants in pregnancy
A full discussion of the risks and ben­efits associated with pharmacotherapy for depression in pregnancy is beyond the scope of this article. Generally, antidepressant use is fraught with concerns over teratogenic­ity and adverse fetal outcomes. Although ACOG states that (1) pharmacotherapy for depression should be individualized and (2) most selective serotonin reuptake inhibi­tors (SSRIs) are not considered major terato­genic agents, many obstetricians and patients feel uncomfortable using these medications in pregnancy.⁴⁰ Often, pre-pregnancy antide­pressants are discontinued in the first trimes­ter; one large population-based study found that only 0.9% of women who had depres­sion filled their antidepressant prescription consistently throughout their pregnancy.⁴¹

It is unclear whether antidepressant use in pregnancy contributes to the risk of preterm birth seen in women who have depression. In a large population-based study, use of antidepressants in the second trimester was associated with preterm delivery but severe depression was not.¹⁸ A recent meta-analysis revealed an increased risk of preterm birth in women who used an antidepressant, com­pared with healthy women and untreated depressed women.⁴²

Research limits, unanswered questions. Regrettably, it is difficult to untangle risk factors for preterm birth among depressed women without randomized controlled studies that are not ethically feasible. It can­not be said with certainty whether antide­pressant pharmacotherapy is associated with a higher risk of preterm birth than depression alone.

Likewise, it is difficult to clarify the extent to which antidepressants contribute to infant growth restriction, if at all. Two recent meta-analyses concluded that exposure to antidepressants is associated with a statisti­cally significant risk of LBW.^42,43 However, increased severity of depressive symptoms generally is associated with exposure to anti­depressants during pregnancy, and a ran­domized controlled trial is, again, impossible to conduct for ethical reasons.

Whereas a plausible biological mecha­nism associating IUGR, SGA, and LBW with depression exists, the same cannot be said for antidepressants. In one study, exposure to maternal depression altered the expres­sion of certain placental genes but exposure to SSRIs did not cause further changes. This suggests that, on a cellular level, placental function might differ in depressed women.⁴⁴ Although antidepressants do cross the pla­centa, it remains to be seen whether fetal growth is impacted as a result. One study found decreased fetal head circumference in infants who had been exposed to antidepres­sants during pregnancy, but no increased risk for having a SGA or LWB infant.⁴⁵

Obstetrical management and mental health implications
Treated or not, women who suffer depres­sion are a high-risk group when it comes to preterm birth and a host of other pregnancy comorbidities. Women with serious compli­cations of pregnancy often are hospitalized for observation, and can undergo a pro­longed stay when close proximity to medical services or a surgical suite is required.

For example, hospitalization until deliv­ery is the standard of care for women who have preterm premature rupture of mem­branes or preeclampsia before 34 weeks’ gestation. Prolonged inpatient admis­sions and associated restriction of activity is profoundly deleterious on mood, with depression and anxiety significantly cor­related with length of stay.^46,47 Given the associations between depression and pre­term birth, it might be reasonable to con­sider screening antenatal inpatients at risk of preterm birth for depression on a regu­lar basis, so that treatment can be initiated if needed.

Depression during pregnancy is rela­tively common; an estimated 12.7% of pregnant women are affected at some time between conception and birth.⁴⁸ Not only does depression appear to have deleterious effects on pregnancy outcomes, it also plays a pivotal role in the qualitative experience of pregnancy for the mother.

Bottom Line
Awareness of obstetrical complications associated with depression in pregnancy is important for the entire care team, including the psychiatrist and obstetrician. Depression not only appears to have deleterious effects on pregnancy outcomes, it also plays a pivotal role in the qualitative experience of pregnancy for the mother. Antidepressant use generally is fraught with concerns over teratogenicity and adverse fetal outcomes.

Related Resources
• Freeman MP. Some SSRIs are better than others for pregnant women (audio interview). Current Psychiatry. 2014;13(7). http://www.currentpsychiatry.com/specialty-focus/practice-trends/article/some-ssris-are-better-thanothers-for-pregnant-women/e3adb4704e25492f3e15331fc1cc058d.html.
• Freeman MP, Joffe H, Cohen LS. Postpartum depression: Help patients find the right treatment. Current Psychiatry. 2012;11(11):14-16,19-21.

Disclosures
Dr. Habecker reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Freeman is a member of the advisory board of JDS Therapeutics, Sunovion Pharmaceuticals, Inc., and Takeda Pharmaceutical Co. She receives research grant support from Takeda Pharmaceutical Co.

When a patient who has a preexisting medical illness seeks prenatal care, the obstetrician asks herself (himself) 2 questions:
   • What impact will the illness have on the pregnancy?
   • What impact will the pregnancy have on the illness?

Depression is both a pregnancy-associated and pregnancy­-independent illness, which, in the setting of a pregnant woman who has a depressive disorder, makes these questions particu­larly difficult to answer. In such a case, coordination of care with a mental health provider is essential.

Awareness of the obstetrical complications associated with depression during pregnancy, as well as their implications for the future health of the mother–infant dyad, is important for the entire care team. This article reviews the associations and interconnectedness of depression with complications of preg­nancy, childbirth, and the neonatal period.

Diagnosis of depression during prenatal care
The American College of Obstetricians and Gynecologists (ACOG) states that evidence is insufficient to support a rec­ommendation for universal screening for depression among prenatal patients, although such screening should be considered.¹ There is considerable variability among obstetrical pro­viders regarding the practice of depression screening; tools to be used if such screening is done; and screening frequency through the pregnancy.

Discernment of depression is difficult. Many somatic symptoms of depression overlap with common prenatal complaints and, consequentially, can be overlooked. Among a sample of 700 pregnant women, for example, 56% complained of lack of energy; 19%, of insomnia; and 19%, of appe­tite changes.² Weight change, of course, is universal.

The 10-question self-rating Edinburgh Postnatal Depression Scale has been vali­dated for use during pregnancy and post­natally. This screening instrument can be helpful for differentiating purely physical complaints from mental distress due to depressive symptoms.^2,3

When an obstetrical provider suspects a depressive disorder, or one has been diagnosed, she (he) faces the problem of what to do with that information. Women of low socioeconomic status and victims of domestic violence are at increased risk of depression during pregnancy, but barri­ers to appropriate referral can seem nearly insurmountable because they lack insur­ance and social support.^4-9

In addition, within the setting of numer­ous tasks that need attending during the relatively short prenatal period, it is com­mon for women newly given a diagnosis of depression to fail to follow up on a refer­ral to a mental health provider.

Although most providers will “check in” with a depressed or at-risk patient at each prenatal visit about her mood, any effort at follow-up can be overshadowed by tangible physical concerns, such as pre­term contractions, fetal growth restriction, and coordination of routine testing that has been delayed because of scant prena­tal care. All these physical concerns and circumstances of care are associated with maternal depression, as we will discuss.

Preterm labor and birth
Preterm labor is defined as uterine contrac­tions that lead to cervical change before 37 weeks gestational age. Preterm labor increases the risk of preterm birth; pre­term labor precedes 50% of preterm births. Preterm birth is the leading cause of neona­tal mortality in the United States, and rates of morbidity and mortality increase as ges­tational age decreases.¹⁰ Common neonatal complications related to prematurity are shown in the Figure.¹¹

Women who suffer from depression have an increased risk of preterm labor and preterm birth, as many studies of treated and untreated depressed pregnant women have shown.^12-20 The causative mechanism is unknown; it has been proposed that the increase in maternal cortisol production asso­ciated with depression and distress triggers overproduction of placental cortisol releasing hormone, which is thought to be involved in initiation of parturition.^21,22 Depression also is associated with other risk factors for preterm birth, such as low socioeconomic status, sub­stance use, and smoking.

Intrauterine growth restriction
Women who have depression during preg­nancy have an increased risk of intrauterine growth restriction (IUGR), which leads to delivery of an infant who is small for ges­tational age (SGA) or of low birth weight (LBW) (weighing <2,500 g at birth), or both.²³ Again, the basis of the association between depression and IUGR and SGA is unknown; it is theorized that increased levels of cortisol and catecholamines associated with maternal distress might, by increasing blood pressure and inducing vasoconstriction, cause placen­tal hypoperfusion.^24,25

It also is possible that the association of depression with other risk factors for IUGR, such as smoking, substance use, obesity, and poor prenatal care, puts the infants of depressed women at risk of growth restric­tion.²⁶ Several large-scale studies showed that the association between LBW and depres­sion is lost when smoking and substance use are accounted for; other studies, however, found a persistent association in untreated depressed women when smokers, substance users, and drinkers were excluded.^17,26,27

IUGR infants are at increased risk of iat­rogenic prematurity and stillbirth. Fetuses that weigh <10th percentile for their ges­tational age are delivered no later than 40 weeks; delivery can be indicated as early as 32 weeks, depending on the results of other antenatal tests. Women who have a growth-restricted infant have a higher risk of cesarean delivery because growth-restricted infants often have less reserve and poorer tolerance of labor.

Preeclampsia and eclampsia
Preeclampsia is defined as blood pressure >140/90 mm HG on at least 2 occasions, with proteinuria, that occurs later than the twentieth week of pregnancy in women who did not have hypertension or renal dysfunction at baseline. Preeclampsia is a progressive disease that can cause severe maternal morbidity, including renal failure, stroke, hepatic rupture, pulmonary edema, and heart failure.

Eclampsia refers to onset of seizures in the setting of preeclampsia. These 2 hyperten­sive disorders are the third leading world wide cause of maternal mortality.²⁸

Depressed women have an elevated risk of preeclampsia. The association between preeclampsia and depression might be caused by the presence of increased levels of inflammatory mediators^29,30; other comorbidities, such as increased body mass index, also might be involved, but the risk for preeclampsia in depressed women still is increased after controlling for obesity.³¹

The presence of preeclampsia is respon­sible for a high percentage of iatrogenic pre­term births, because the cure for the disorder is delivery—even at early or previable gesta­tional age. Complication rates for mother and infant are high.

The presence of preeclampsia is a sig­nificant risk factor for intrauterine fetal demise. Treating the mother after delivery involves administration of IV magnesium for 24 hours; often, the mother is separated from her infant for a day after birth.

Impact on prenatal care
Depression increases odds that women will have fewer prenatal visits.³² During pregnancy, women typically initiate pre­natal care during the first trimester, when pregnancy-dating ultrasonography and early screening tests for chromosomal abnormalities are performed. Prenatal vis­its occur monthly until the third trimes­ter, then every 2 weeks between 32 and 36 weeks’ gestation, increasing to weekly after 36 weeks’ gestation.

The increased number of visits in late pregnancy allows for early detection and treatment of hypertensive disorders; assesses fetal well-being; and decreases the risks of morbidity and mortality for mother and fetus.³³ Because women who suffer from depression are at increased risk of an array of adverse pregnancy outcomes, the impor­tance of regular and timely prenatal care cannot be understated.

In addition, the prenatal visit gives the obstetrician the opportunity to connect women with other specialists for manage­ment of any unmet medical needs. One study showed that, when women have adequate prenatal care (measured by the number of visits), the association between preterm birth and self-reported maternal depression was eliminated.³⁴

Substance use
Substance use and depression often co-exist.^35,36 Unlike screening for depression, screening for substance use is universal dur­ing prenatal care. Studies have shown that women who screen positive for depression are at higher risk of a number of comorbidi­ties, including substance use.^37,38 Conversely, women who use substances are more likely to screen positive for depression.

Evidence suggests that best practice might be to screen for depression in any woman who has a positive drug screen, if a provider is not routinely screening their general patient population.³⁹ Substance use in pregnancy is associated with a number of poor outcomes, including placental abrup­tion (cocaine use); dysmorphic facies and congenital anomalies (alcohol); and neonatal abstinence syndrome (heroin).

Antidepressants in pregnancy
A full discussion of the risks and ben­efits associated with pharmacotherapy for depression in pregnancy is beyond the scope of this article. Generally, antidepressant use is fraught with concerns over teratogenic­ity and adverse fetal outcomes. Although ACOG states that (1) pharmacotherapy for depression should be individualized and (2) most selective serotonin reuptake inhibi­tors (SSRIs) are not considered major terato­genic agents, many obstetricians and patients feel uncomfortable using these medications in pregnancy.⁴⁰ Often, pre-pregnancy antide­pressants are discontinued in the first trimes­ter; one large population-based study found that only 0.9% of women who had depres­sion filled their antidepressant prescription consistently throughout their pregnancy.⁴¹

It is unclear whether antidepressant use in pregnancy contributes to the risk of preterm birth seen in women who have depression. In a large population-based study, use of antidepressants in the second trimester was associated with preterm delivery but severe depression was not.¹⁸ A recent meta-analysis revealed an increased risk of preterm birth in women who used an antidepressant, com­pared with healthy women and untreated depressed women.⁴²

Research limits, unanswered questions. Regrettably, it is difficult to untangle risk factors for preterm birth among depressed women without randomized controlled studies that are not ethically feasible. It can­not be said with certainty whether antide­pressant pharmacotherapy is associated with a higher risk of preterm birth than depression alone.

Likewise, it is difficult to clarify the extent to which antidepressants contribute to infant growth restriction, if at all. Two recent meta-analyses concluded that exposure to antidepressants is associated with a statisti­cally significant risk of LBW.^42,43 However, increased severity of depressive symptoms generally is associated with exposure to anti­depressants during pregnancy, and a ran­domized controlled trial is, again, impossible to conduct for ethical reasons.

Whereas a plausible biological mecha­nism associating IUGR, SGA, and LBW with depression exists, the same cannot be said for antidepressants. In one study, exposure to maternal depression altered the expres­sion of certain placental genes but exposure to SSRIs did not cause further changes. This suggests that, on a cellular level, placental function might differ in depressed women.⁴⁴ Although antidepressants do cross the pla­centa, it remains to be seen whether fetal growth is impacted as a result. One study found decreased fetal head circumference in infants who had been exposed to antidepres­sants during pregnancy, but no increased risk for having a SGA or LWB infant.⁴⁵

Obstetrical management and mental health implications
Treated or not, women who suffer depres­sion are a high-risk group when it comes to preterm birth and a host of other pregnancy comorbidities. Women with serious compli­cations of pregnancy often are hospitalized for observation, and can undergo a pro­longed stay when close proximity to medical services or a surgical suite is required.

For example, hospitalization until deliv­ery is the standard of care for women who have preterm premature rupture of mem­branes or preeclampsia before 34 weeks’ gestation. Prolonged inpatient admis­sions and associated restriction of activity is profoundly deleterious on mood, with depression and anxiety significantly cor­related with length of stay.^46,47 Given the associations between depression and pre­term birth, it might be reasonable to con­sider screening antenatal inpatients at risk of preterm birth for depression on a regu­lar basis, so that treatment can be initiated if needed.

Depression during pregnancy is rela­tively common; an estimated 12.7% of pregnant women are affected at some time between conception and birth.⁴⁸ Not only does depression appear to have deleterious effects on pregnancy outcomes, it also plays a pivotal role in the qualitative experience of pregnancy for the mother.

Bottom Line
Awareness of obstetrical complications associated with depression in pregnancy is important for the entire care team, including the psychiatrist and obstetrician. Depression not only appears to have deleterious effects on pregnancy outcomes, it also plays a pivotal role in the qualitative experience of pregnancy for the mother. Antidepressant use generally is fraught with concerns over teratogenicity and adverse fetal outcomes.

Related Resources
• Freeman MP. Some SSRIs are better than others for pregnant women (audio interview). Current Psychiatry. 2014;13(7). http://www.currentpsychiatry.com/specialty-focus/practice-trends/article/some-ssris-are-better-thanothers-for-pregnant-women/e3adb4704e25492f3e15331fc1cc058d.html.
• Freeman MP, Joffe H, Cohen LS. Postpartum depression: Help patients find the right treatment. Current Psychiatry. 2012;11(11):14-16,19-21.

Disclosures
Dr. Habecker reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Freeman is a member of the advisory board of JDS Therapeutics, Sunovion Pharmaceuticals, Inc., and Takeda Pharmaceutical Co. She receives research grant support from Takeda Pharmaceutical Co.

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