Clinical Review

Reaching the correct diagnosis of ventilator-associated pneumonia (VAP) can be a considerable challenge for physicians. Many conditions seem similar to VAP, say researchers from Chi Mei Medical Center in Tainan, Taiwan. Moreover, the conventional definition of VAP relies on clinical, radiologic, and microbiologic findings that may be interpreted differently by different clinicians.

In 2013, the CDC National Healthcare Safety Network developed a novel approach to surveillance for ventilator-associated events (VAEs) to better improve the objectivity and reproducibility of VAP surveillance. The new algorithm defines VAEs with a combination of “objective, streamlined, and potentially automatable criteria,” including deterioration in respiratory status after a period of stability or improvement on the ventilator.

Related: NSAIDs Linked to Poor Pneumonia Outcomes

But does the new method outperform the old? In their retrospective study, which analyzed 165 episodes of VAP, the researchers compared the new method with conventional paradigms and found novel VAE surveillance detected only 33.3% of conventional VAP cases. This study suggests that the concordance between the new algorithm and conventional VAP surveillance is poor, the researchers said. They advise more studies to further validate VAE surveillance.

Sources
Chang HC, Chen CM, Kung SC, Wang CM, Liu WL, Lai CC. Am J Infect Control. 2015;43(2):133-136.
doi: 10.1016/j.ajic.2014.10.029.

Centers for Disease Control and Prevention. Ventilator-Associated Event (VAE) Protocol. Atlanta, GA: Centers for Disease Control and Prevention, U.S. Dept of Health and Human Services; 2015.

Reaching the correct diagnosis of ventilator-associated pneumonia (VAP) can be a considerable challenge for physicians. Many conditions seem similar to VAP, say researchers from Chi Mei Medical Center in Tainan, Taiwan. Moreover, the conventional definition of VAP relies on clinical, radiologic, and microbiologic findings that may be interpreted differently by different clinicians.

In 2013, the CDC National Healthcare Safety Network developed a novel approach to surveillance for ventilator-associated events (VAEs) to better improve the objectivity and reproducibility of VAP surveillance. The new algorithm defines VAEs with a combination of “objective, streamlined, and potentially automatable criteria,” including deterioration in respiratory status after a period of stability or improvement on the ventilator.

Related: NSAIDs Linked to Poor Pneumonia Outcomes

But does the new method outperform the old? In their retrospective study, which analyzed 165 episodes of VAP, the researchers compared the new method with conventional paradigms and found novel VAE surveillance detected only 33.3% of conventional VAP cases. This study suggests that the concordance between the new algorithm and conventional VAP surveillance is poor, the researchers said. They advise more studies to further validate VAE surveillance.

Sources
Chang HC, Chen CM, Kung SC, Wang CM, Liu WL, Lai CC. Am J Infect Control. 2015;43(2):133-136.
doi: 10.1016/j.ajic.2014.10.029.

Centers for Disease Control and Prevention. Ventilator-Associated Event (VAE) Protocol. Atlanta, GA: Centers for Disease Control and Prevention, U.S. Dept of Health and Human Services; 2015.

Reaching the correct diagnosis of ventilator-associated pneumonia (VAP) can be a considerable challenge for physicians. Many conditions seem similar to VAP, say researchers from Chi Mei Medical Center in Tainan, Taiwan. Moreover, the conventional definition of VAP relies on clinical, radiologic, and microbiologic findings that may be interpreted differently by different clinicians.

In 2013, the CDC National Healthcare Safety Network developed a novel approach to surveillance for ventilator-associated events (VAEs) to better improve the objectivity and reproducibility of VAP surveillance. The new algorithm defines VAEs with a combination of “objective, streamlined, and potentially automatable criteria,” including deterioration in respiratory status after a period of stability or improvement on the ventilator.

Related: NSAIDs Linked to Poor Pneumonia Outcomes

But does the new method outperform the old? In their retrospective study, which analyzed 165 episodes of VAP, the researchers compared the new method with conventional paradigms and found novel VAE surveillance detected only 33.3% of conventional VAP cases. This study suggests that the concordance between the new algorithm and conventional VAP surveillance is poor, the researchers said. They advise more studies to further validate VAE surveillance.

Sources
Chang HC, Chen CM, Kung SC, Wang CM, Liu WL, Lai CC. Am J Infect Control. 2015;43(2):133-136.
doi: 10.1016/j.ajic.2014.10.029.

Centers for Disease Control and Prevention. Ventilator-Associated Event (VAE) Protocol. Atlanta, GA: Centers for Disease Control and Prevention, U.S. Dept of Health and Human Services; 2015.

THE CASE

A 31-year-old man came to an internal medicine clinic because he’d been losing weight over the past 2 years and hadn’t been able to regain any weight despite eating properly. Our patient was born in Ethiopia, but had been living in Canada for 6 years. He reported a remote history of 2 episodes of diarrhea.

His physical exam was normal and laboratory results revealed mild eosinophilia of 0.6 × 10⁹/L (normal range, <0.45 × 10⁹/L). Additional tests (including complete blood count, electrolytes, liver panel, thyrotropin, and blood smear) revealed no apparent metabolic causes of the patient’s weight loss. Stool analysis (3 exams) was negative for ova and parasites.

THE DIAGNOSIS

Because our patient was born in Ethiopia, we did serologic testing for Strongyloides, which was positive (enzyme-linked immunosorbent assay for immunoglobulin G antibodies [IgG-ELISA] was 2.9; positive is >2.1). We diagnosed strongyloidiasis in this patient.

DISCUSSION

Strongyloidiasis is an infection caused by the parasite Strongyloides stercoralis.¹ It affects an estimated 30 to 100 million people worldwide, mainly in Africa, Southeast Asia, Central America, and South America, but it also can occur in temperate climates.²Strongyloides is a soil-transmitted helminth (parasitic worm). The prevalence of Strongyloides infection among refugee groups in the United States is 1% to 4.3%.^3-5

Although patients with strongyloidiasis are often asymptomatic, they can present with a wide range of nonspecific symptoms. In the acute stage, patients may develop signs and symptoms including cough, wheeze, abdominal pain, weight loss, diarrhea, pruritus ani, and larva currens.² Respiratory symptoms, including tracheal irritation and a dry cough, are often confused with asthma. In the generally asymptomatic chronic stage, patients may develop gastrointestinal complaints, such as epigastric pain and heartburn.⁶

Hyperinfection syndrome can occur when patients with subclinical infection receive high doses of corticosteroids for asthma or chronic obstructive pulmonary disease exacerbations. Risk of hyperinfection is increased among immunocompromised patients with human T lymphotropic virus type-1 (HTLV-1),⁷ as well as in patients with malignancies, malnutrition, and alcohol use disorder. Eosinophilia is often absent in patients with hyperinfection, and stool examination results are almost always positive.⁸

Who to screen, how to make the diagnosis

Suspect strongyloidiasis infection in immigrants, refugees, and travelers from endemic regions who have eosinophilia. The presence of eosinophilia in immigrants, refugees, and travelers from endemic regions should alert clinicians to the possibility of an underlying helminth infection. However, because eosinophilia occurs intermittently in response to tissue invasion, absence of eosinophilia does not exclude strongyloidiasis.

The Canadian Collaboration for Immigrants and Refugee Health (CCIRH) recommends using serologic testing to screen for Strongyloides in all newly arrived refugees from low-income countries in Southeast Asia and Africa.⁹ The CCIRH also advises that while data on the burden of strongyloidiasis in non-refugee immigrant populations is limited, you should consider screening foreign-born individuals who have lived in endemic areas, have symptoms and/or signs of Strongyloides infection, and/or have evidence of eosinophilia.⁹ Because the risk of hyperinfection is increased in immunocompromised individuals, screening should be done to detect Strongyloides infection before starting chemotherapy and before initiating corticosteroids in patients from endemic areas.¹⁰

Diagnostic methods. Stool examination⁶ and IgG-ELISA² are the main methods used to diagnose strongyloidiasis. However, traditional stool examinations have low sensitivity, and it may require up to 7 stool exams to reach a sensitivity of 100%,⁶ which could explain why our patient’s stool analysis was negative for parasites. In our experience, a positive serology result should always be assumed to indicate an active infection unless there is a well documented history of prior therapy. (In such cases, a positive serology result could represent persistent antibodies following therapy.)

First-line therapy and alternative treatment

All patients with strongyloidiasis, regardless of whether they are symptomatic, must be treated to prevent possible late-onset disseminated disease and hyperinfection.⁹ The Centers for Disease Control and Prevention recommends one to 2 doses of ivermectin 200 mcg/kg as first-line therapy or albendazole 400 mg twice daily for 3 days as an alternative treatment (TABLE).¹¹ Ivermectin cures more than 95% of cases.¹² Albendazole has lower efficacy (78%).¹³ Some experts recommend administering the 2 doses of ivermectin 2 weeks apart to allow enough time for the parasite to migrate to the gut.⁴

Consider referral to an infectious disease specialist for patients coinfected with HTLV-1, as well as those who are immunocompromised. Coinfection with HTLV-1 (which is endemic in areas where Strongyloides also is
endemic) modifies patients’ immune response and can complicate treatment.⁹ Clinicians should screen strongyloidiasis patients for HTLV-1 if they come from high-prevalence areas and/or have persistent strongyloidiasis that responds poorly to antiparasitic treatment.⁹

Consider referral to an infectious disease specialist for patients coinfected with
HTLV-1, as well as those who are immunocompromised. Such referral also may be appropriate for patients from countries where loa loa is endemic, because encephalopathy has occurred in patients coinfected with loa loa who were treated with ivermectin.¹⁰

Our patient was treated with 2 doses of ivermectin 200 mcg/kg, 2 weeks apart. Four months later, his eosinophilia had resolved, his IgG-ELISA dropped to 0.37, and he had gained 2.5 pounds.

THE TAKEAWAY

Strongyloidiasis is an infection caused by the parasitic worm Strongyloides stercoralis that is most common in tropical or subtropical areas. It can be asymptomatic or present with a wide range of nonspecific signs and symptoms, such as eosinophilia, cough, wheeze, abdominal pain, weight loss, diarrhea, pruritus ani, and larva currens. It is diagnosed by stool examination and serologic testing. Ivermectin is first-line therapy; albendazole is an alternative.

THE CASE

A 31-year-old man came to an internal medicine clinic because he’d been losing weight over the past 2 years and hadn’t been able to regain any weight despite eating properly. Our patient was born in Ethiopia, but had been living in Canada for 6 years. He reported a remote history of 2 episodes of diarrhea.

His physical exam was normal and laboratory results revealed mild eosinophilia of 0.6 × 10⁹/L (normal range, <0.45 × 10⁹/L). Additional tests (including complete blood count, electrolytes, liver panel, thyrotropin, and blood smear) revealed no apparent metabolic causes of the patient’s weight loss. Stool analysis (3 exams) was negative for ova and parasites.

THE DIAGNOSIS

Because our patient was born in Ethiopia, we did serologic testing for Strongyloides, which was positive (enzyme-linked immunosorbent assay for immunoglobulin G antibodies [IgG-ELISA] was 2.9; positive is >2.1). We diagnosed strongyloidiasis in this patient.

DISCUSSION

Strongyloidiasis is an infection caused by the parasite Strongyloides stercoralis.¹ It affects an estimated 30 to 100 million people worldwide, mainly in Africa, Southeast Asia, Central America, and South America, but it also can occur in temperate climates.²Strongyloides is a soil-transmitted helminth (parasitic worm). The prevalence of Strongyloides infection among refugee groups in the United States is 1% to 4.3%.^3-5

Although patients with strongyloidiasis are often asymptomatic, they can present with a wide range of nonspecific symptoms. In the acute stage, patients may develop signs and symptoms including cough, wheeze, abdominal pain, weight loss, diarrhea, pruritus ani, and larva currens.² Respiratory symptoms, including tracheal irritation and a dry cough, are often confused with asthma. In the generally asymptomatic chronic stage, patients may develop gastrointestinal complaints, such as epigastric pain and heartburn.⁶

Hyperinfection syndrome can occur when patients with subclinical infection receive high doses of corticosteroids for asthma or chronic obstructive pulmonary disease exacerbations. Risk of hyperinfection is increased among immunocompromised patients with human T lymphotropic virus type-1 (HTLV-1),⁷ as well as in patients with malignancies, malnutrition, and alcohol use disorder. Eosinophilia is often absent in patients with hyperinfection, and stool examination results are almost always positive.⁸

Who to screen, how to make the diagnosis

Suspect strongyloidiasis infection in immigrants, refugees, and travelers from endemic regions who have eosinophilia. The presence of eosinophilia in immigrants, refugees, and travelers from endemic regions should alert clinicians to the possibility of an underlying helminth infection. However, because eosinophilia occurs intermittently in response to tissue invasion, absence of eosinophilia does not exclude strongyloidiasis.

The Canadian Collaboration for Immigrants and Refugee Health (CCIRH) recommends using serologic testing to screen for Strongyloides in all newly arrived refugees from low-income countries in Southeast Asia and Africa.⁹ The CCIRH also advises that while data on the burden of strongyloidiasis in non-refugee immigrant populations is limited, you should consider screening foreign-born individuals who have lived in endemic areas, have symptoms and/or signs of Strongyloides infection, and/or have evidence of eosinophilia.⁹ Because the risk of hyperinfection is increased in immunocompromised individuals, screening should be done to detect Strongyloides infection before starting chemotherapy and before initiating corticosteroids in patients from endemic areas.¹⁰

Diagnostic methods. Stool examination⁶ and IgG-ELISA² are the main methods used to diagnose strongyloidiasis. However, traditional stool examinations have low sensitivity, and it may require up to 7 stool exams to reach a sensitivity of 100%,⁶ which could explain why our patient’s stool analysis was negative for parasites. In our experience, a positive serology result should always be assumed to indicate an active infection unless there is a well documented history of prior therapy. (In such cases, a positive serology result could represent persistent antibodies following therapy.)

First-line therapy and alternative treatment

All patients with strongyloidiasis, regardless of whether they are symptomatic, must be treated to prevent possible late-onset disseminated disease and hyperinfection.⁹ The Centers for Disease Control and Prevention recommends one to 2 doses of ivermectin 200 mcg/kg as first-line therapy or albendazole 400 mg twice daily for 3 days as an alternative treatment (TABLE).¹¹ Ivermectin cures more than 95% of cases.¹² Albendazole has lower efficacy (78%).¹³ Some experts recommend administering the 2 doses of ivermectin 2 weeks apart to allow enough time for the parasite to migrate to the gut.⁴

Consider referral to an infectious disease specialist for patients coinfected with HTLV-1, as well as those who are immunocompromised. Coinfection with HTLV-1 (which is endemic in areas where Strongyloides also is
endemic) modifies patients’ immune response and can complicate treatment.⁹ Clinicians should screen strongyloidiasis patients for HTLV-1 if they come from high-prevalence areas and/or have persistent strongyloidiasis that responds poorly to antiparasitic treatment.⁹

Consider referral to an infectious disease specialist for patients coinfected with
HTLV-1, as well as those who are immunocompromised. Such referral also may be appropriate for patients from countries where loa loa is endemic, because encephalopathy has occurred in patients coinfected with loa loa who were treated with ivermectin.¹⁰

Our patient was treated with 2 doses of ivermectin 200 mcg/kg, 2 weeks apart. Four months later, his eosinophilia had resolved, his IgG-ELISA dropped to 0.37, and he had gained 2.5 pounds.

THE TAKEAWAY

Strongyloidiasis is an infection caused by the parasitic worm Strongyloides stercoralis that is most common in tropical or subtropical areas. It can be asymptomatic or present with a wide range of nonspecific signs and symptoms, such as eosinophilia, cough, wheeze, abdominal pain, weight loss, diarrhea, pruritus ani, and larva currens. It is diagnosed by stool examination and serologic testing. Ivermectin is first-line therapy; albendazole is an alternative.

THE CASE

A 31-year-old man came to an internal medicine clinic because he’d been losing weight over the past 2 years and hadn’t been able to regain any weight despite eating properly. Our patient was born in Ethiopia, but had been living in Canada for 6 years. He reported a remote history of 2 episodes of diarrhea.

His physical exam was normal and laboratory results revealed mild eosinophilia of 0.6 × 10⁹/L (normal range, <0.45 × 10⁹/L). Additional tests (including complete blood count, electrolytes, liver panel, thyrotropin, and blood smear) revealed no apparent metabolic causes of the patient’s weight loss. Stool analysis (3 exams) was negative for ova and parasites.

THE DIAGNOSIS

Because our patient was born in Ethiopia, we did serologic testing for Strongyloides, which was positive (enzyme-linked immunosorbent assay for immunoglobulin G antibodies [IgG-ELISA] was 2.9; positive is >2.1). We diagnosed strongyloidiasis in this patient.

DISCUSSION

Strongyloidiasis is an infection caused by the parasite Strongyloides stercoralis.¹ It affects an estimated 30 to 100 million people worldwide, mainly in Africa, Southeast Asia, Central America, and South America, but it also can occur in temperate climates.²Strongyloides is a soil-transmitted helminth (parasitic worm). The prevalence of Strongyloides infection among refugee groups in the United States is 1% to 4.3%.^3-5

Although patients with strongyloidiasis are often asymptomatic, they can present with a wide range of nonspecific symptoms. In the acute stage, patients may develop signs and symptoms including cough, wheeze, abdominal pain, weight loss, diarrhea, pruritus ani, and larva currens.² Respiratory symptoms, including tracheal irritation and a dry cough, are often confused with asthma. In the generally asymptomatic chronic stage, patients may develop gastrointestinal complaints, such as epigastric pain and heartburn.⁶

Hyperinfection syndrome can occur when patients with subclinical infection receive high doses of corticosteroids for asthma or chronic obstructive pulmonary disease exacerbations. Risk of hyperinfection is increased among immunocompromised patients with human T lymphotropic virus type-1 (HTLV-1),⁷ as well as in patients with malignancies, malnutrition, and alcohol use disorder. Eosinophilia is often absent in patients with hyperinfection, and stool examination results are almost always positive.⁸

Who to screen, how to make the diagnosis

Suspect strongyloidiasis infection in immigrants, refugees, and travelers from endemic regions who have eosinophilia. The presence of eosinophilia in immigrants, refugees, and travelers from endemic regions should alert clinicians to the possibility of an underlying helminth infection. However, because eosinophilia occurs intermittently in response to tissue invasion, absence of eosinophilia does not exclude strongyloidiasis.

The Canadian Collaboration for Immigrants and Refugee Health (CCIRH) recommends using serologic testing to screen for Strongyloides in all newly arrived refugees from low-income countries in Southeast Asia and Africa.⁹ The CCIRH also advises that while data on the burden of strongyloidiasis in non-refugee immigrant populations is limited, you should consider screening foreign-born individuals who have lived in endemic areas, have symptoms and/or signs of Strongyloides infection, and/or have evidence of eosinophilia.⁹ Because the risk of hyperinfection is increased in immunocompromised individuals, screening should be done to detect Strongyloides infection before starting chemotherapy and before initiating corticosteroids in patients from endemic areas.¹⁰

Diagnostic methods. Stool examination⁶ and IgG-ELISA² are the main methods used to diagnose strongyloidiasis. However, traditional stool examinations have low sensitivity, and it may require up to 7 stool exams to reach a sensitivity of 100%,⁶ which could explain why our patient’s stool analysis was negative for parasites. In our experience, a positive serology result should always be assumed to indicate an active infection unless there is a well documented history of prior therapy. (In such cases, a positive serology result could represent persistent antibodies following therapy.)

First-line therapy and alternative treatment

All patients with strongyloidiasis, regardless of whether they are symptomatic, must be treated to prevent possible late-onset disseminated disease and hyperinfection.⁹ The Centers for Disease Control and Prevention recommends one to 2 doses of ivermectin 200 mcg/kg as first-line therapy or albendazole 400 mg twice daily for 3 days as an alternative treatment (TABLE).¹¹ Ivermectin cures more than 95% of cases.¹² Albendazole has lower efficacy (78%).¹³ Some experts recommend administering the 2 doses of ivermectin 2 weeks apart to allow enough time for the parasite to migrate to the gut.⁴

Consider referral to an infectious disease specialist for patients coinfected with HTLV-1, as well as those who are immunocompromised. Coinfection with HTLV-1 (which is endemic in areas where Strongyloides also is
endemic) modifies patients’ immune response and can complicate treatment.⁹ Clinicians should screen strongyloidiasis patients for HTLV-1 if they come from high-prevalence areas and/or have persistent strongyloidiasis that responds poorly to antiparasitic treatment.⁹

Consider referral to an infectious disease specialist for patients coinfected with
HTLV-1, as well as those who are immunocompromised. Such referral also may be appropriate for patients from countries where loa loa is endemic, because encephalopathy has occurred in patients coinfected with loa loa who were treated with ivermectin.¹⁰

Our patient was treated with 2 doses of ivermectin 200 mcg/kg, 2 weeks apart. Four months later, his eosinophilia had resolved, his IgG-ELISA dropped to 0.37, and he had gained 2.5 pounds.

THE TAKEAWAY

Strongyloidiasis is an infection caused by the parasitic worm Strongyloides stercoralis that is most common in tropical or subtropical areas. It can be asymptomatic or present with a wide range of nonspecific signs and symptoms, such as eosinophilia, cough, wheeze, abdominal pain, weight loss, diarrhea, pruritus ani, and larva currens. It is diagnosed by stool examination and serologic testing. Ivermectin is first-line therapy; albendazole is an alternative.

A switch to hydromorphone 20 mg/d—the physician used the 5:1 morphine-to-hydromorphone conversion ratio, then decreased the dose by 50% to account for incomplete cross-tolerance—left Ms. G lethargic. In addition, her pain score rose to 5, and she began having difficulty swallowing the medication. Prior to the drug rotation, she was able to perform light tasks and was alert enough to interact with her family.

If Ms. G were your patient, what would be your next step?

By bypassing 
first-pass metabolism, intrathecal drug delivery provides greater pain relief at lower dosages and with fewer adverse effects than systemic delivery. Continuous intrathecal (IT) drug delivery systems have been in use for more than 30 years.¹ And, while IT administration of analgesia has become increasingly useful for patients with refractory chronic pain and spasticity, it remains an underutilized resource.² Delivered directly into the pre- and post-synaptic opioid receptors in the dorsal horn of the spinal cord, IT analgesia bypasses first-pass metabolism. The result: a higher rate of efficacy, with smaller dosages and fewer adverse effects than systemic delivery.¹

The drugs are delivered via a small battery-powered programmable pump that is implanted under the subcutaneous tissue of the abdomen and connected to a catheter tunneled to the site of spinal entry. The device must be refilled periodically—typically every one to 3 months—but this is not a difficult process. It can be done in an office setting or in the patient’s home by a specially trained visiting nurse.³

There is ample reason to consider this approach when systemic analgesics or antispasmodics fail to control pain or cause unacceptable adverse effects. So why isn’t it used more frequently? One factor may be that many primary care physicians—often the first practitioners called upon to manage these complicated cases—know too little about it.

Who is a potential candidate for IT analgesia? What medications can be administered via this route? What is the role of a family physician (FP) in coordinating and overseeing the care of a patient being treated with IT therapy? Our goals in writing this review are to address these questions.

Patient selection: Not just for cancer pain

Because of the invasive nature and high cost of implantation, intrathecal pumps are typically reserved for patients with a life expectancy of more than 6 months. FPs interested in referring patients for IT therapy have many factors to consider before consulting a pain specialist. Foremost among them are the different criteria for individuals with cancer-related pain and those with chronic nonmalignant pain.

IT analgesia for cancer pain has been shown to improve patients’ quality of life and potentially increase long-term survival due to a decrease in systemic toxicity.^4-6 An appropriate candidate is an individual who, like Ms. G, was initially responsive to systemic opioids but later developed refractory symptoms or intolerance.⁷ Because of the invasive nature and high cost of implantation, subcutaneous IT pumps are typically reserved for patients with a life expectancy of more than 6 months.⁷ But implantation may be considered for those with a shorter life expectancy if they have severe pain or cannot tolerate the adverse effects of systemic analgesia.

Noncancer pain is more complex

The use of IT analgesia in patients with chronic nonmalignant pain, such as failed back surgery syndrome, spasticity associated with multiple sclerosis, or diabetic neuropathy, is both more controversial and more complex. It is important for FPs to recognize the multidimensional nature of this type of pain, which may be complicated by physical, psychological, and behavioral factors, including the possibility of addiction.^8-11

Although IT analgesia is less subject to abuse and diversion than systemic opioids, the dependent relationship associated with a continuous delivery system makes risk stratification a necessity.¹² Psychological testing is commonly used to evaluate potential candidates for long-term IT analgesia.

Prior to placement, patients must have had a failed course of conservative pain management and have no surgical options, no medical contraindications (eg, spinal pathology or susceptibility to infection), and no evidence of active addiction.¹² A medication history is crucial, too, to identify use of anticoagulation therapy—a relative contraindication—as well as drug allergies and potential drug-drug interactions to guard against.³

An IT trial may be required

Psychological testing is commonly used to evaluate potential candidates for long-term intrathecal analgesia. It is common practice for patients to undergo an IT analgesia trial prior to implantation of a subcutaneous pump. This involves using an external pump to infuse the selected medication intrathecally and slowly titrating it according to symptoms for 2 to 3 days. During this time frame, the patient records his or her response; a reduction by more than half in VAS pain score is considered a success, indicating that the patient is an appropriate candidate for placement of the device.^3,13

Drug choices—a look at the evidence

The US Food and Drug Administration (FDA) has approved 3 medications for continuous IT delivery: morphine, ziconotide, and baclofen. But it is common practice to use alternative agents, such as other opioids, local anesthetics, or alpha 2-adrenergic agonists (TABLE).^3,14-34 

CASE  › Ms. G’s primary care physician referred her to a pain specialist, who thought she would benefit from IT analgesia. After a successful single-shot IT trial with 0.5 mg morphine, the patient underwent implantation.  The specialist chose morphine as the IT agent because of Ms. G’s history of successful pain relief with it, and because such a low dose was unlikely to be a problem for a patient with renal failure.

A month later, when she returned to the specialist to have the pump refilled, Ms. G reported a pain score of 3.

Opioids such as morphine exhibit a wider spread of analgesia when administered intrathecally, resulting in fewer adverse effects than systemic opioids.^13,35,36 The mu-opioid receptors in the dorsal horn of the spinal cord are the primary target of IT opioids.

In a multicenter randomized trial involving 200 cancer patients on opioids, Smith et al⁴ compared implantable IT drug delivery systems with comprehensive medical management. The mean VAS pain score in the IT group fell 52% vs a decline of 39% in the medical management group. 

The evidence supporting IT opioids for nonmalignant pain is not as strong. This may be due to inherent differences in pain mechanisms. In cancer pain, between 75% and 90% of pain is either nociceptive or mixed nociceptive-neuropathic; the etiology of noncancer pain is more variable.^37-39 

Although IT opioid therapy is associated with a lower incidence of adverse effects than systemic therapy, this route is not devoid of adverse effects. Opioids delivered intrathecally may still be associated with respiratory depression, constipation, urinary retention, nausea/vomiting, sweating, and hyperalgesia.³⁹ In addition, chronic opioid use suppresses the hypothalamic-pituitary-gonadal axis and the hypothalamic-pituitary-adrenal axis^14,40,41—a risk with long-term IT as well as systemic administration.¹⁴  Respiratory depression most commonly results from accidental overdosing, and patients must be monitored during initiation and dose escalation of IT opioid therapy.¹⁵

Local anesthetics. Numerous studies have documented the favorable outcomes of combining local anesthetics with opioids for patients with cancer^16-20 and noncancer pain.^21,22 Local anesthetics work via the blockade of voltage-gated sodium channels, interfering with neuron depolarization.¹⁷

Numerous studies have documented the favorable outcomes of combining local anesthetics with opioids for cancer and noncancer pain. A retrospective study in which patients with malignant pain and those with failed back surgery syndrome had bupivacaine added to their IT opioid solution found that the combination led to lower pain scores and a 23% reduction in opioid dosage.²⁰ In another retrospective review, researchers demonstrated that the coadministration of IT bupivacaine and an opioid decreased the rate of opioid dose escalation by 65% over the first year in patients with noncancer pain.²³

However, a double-blind randomized, crossover multicenter study found that in patients with chronic nonmalignant pain, the addition of bupivacaine to IT opioids failed to produce significant improvement in pain control compared with opioid use alone. Quality of life scores did improve, however, in the group receiving combination therapy.²⁴

Adverse effects of local anesthetics delivered intrathecally include numbness, paresthesias, weakness, bowel/bladder dysfunction, and neurotoxicity.^17,19,25  

Calcium channel blockers. Found in venom produced by the marine snail Conus magus, ziconotide blocks presynaptic N-type channels. It is the only calcium channel blocker used to manage chronic pain.²⁶ Several trials in patients with malignant and nonmalignant pain have shown a significant decrease in VAS pain scores compared with placebo.^25,26 In addition, a multicenter, double-blind placebo-controlled crossover study evaluating IT ziconotide for the treatment of refractory pain in 111 patients with cancer and AIDS found that the treatment group obtained significantly better pain relief than the controls (53% vs 17.5% using a VAS pain intensity score).²⁵ However, 31% of those in the treatment group experienced adverse effects, the most common of which were confusion, somnolence, and urinary retention.

Ziconotide has FDA approval only as monotherapy. But because of its high cost and adverse effect profile, it is mainly used in combination with other IT drugs.²⁷ Ziconotide increases the risk of suicide in patients with a history of depression.²⁸ The prevalence of adverse effects correlates with a higher dose, faster titration rate, and older age.^26,28

Alpha-2 adrenergic agonists. Clonidine is the only alpha-2 agonist with FDA approval for epidural use, with several studies supporting its off-label use in combination with IT therapy.^22,29 In a prospective open-label study evaluating combination IT therapy in patients with failed back surgery syndrome, 73% reported subjective ratings of good or excellent at 2-year follow-up.²² The most common adverse effects were sedation, hypotension, nausea, and dry mouth.

Gamma-aminobutyric acid (GABA) agonists. Baclofen, a GABA agonist with FDA approval for the treatment of spasticity, has been used intrathecally since the mid-1980s.³² Several studies have supported its effectiveness for this purpose.^30,42  Clinical studies have also found IT baclofen to be effective in treating conditions such as complex regional pain syndrome, central pain, and neuropathic pain secondary to failed back surgery syndrome.^31,32 In one randomized double-blind crossover trial, 7 women with complex regional pain syndrome were given bolus injections of baclofen or saline. Those treated with baclofen experienced a reduction in pain and regained function.³¹

In another trial—a double-blind placebo-controlled study of patients with multiple sclerosis and spinal cord injury comparing baclofen with placebo—those treated with baclofen showed significant reductions in dysesthetic and spasm-related pain.³² The most common adverse effects of baclofen are drowsiness, cognitive impairment, weakness, gastrointestinal complaints, and sexual dysfunction.³¹

Which patients and which drugs? An expert consensus

Due to the potential for inconsistent patient management and the use of therapies with anecdotal evidence, the Polyanalgesic Consensus Conference (PACC)—a panel of experts in IT therapy—convened in 2000, 2003, 2007, and 2011 to develop recommendations for IT therapy and an algorithm for drug selection. PACC’s list of chronic conditions for which IT should be considered includes axial low back pain, postherpetic neuralgia, spinal cord injury, spinal stenosis, pancreatitis, osteoporosis, compression fracture, and phantom limb pain, among others.

The algorithm contains separate arms for neuropathic, nociceptive, and mixed pain states. First-line agents for neuropathic pain include morphine, alone or combined with bupivacaine, and ziconotide. For nociceptive pain, morphine, hydromorphone, fentanyl, and ziconotide are all first-line agents; for mixed pain states, the appropriate choice should be based on the clinical scenario.³³

Overseeing IT pain management in primary care

Referring potential candidates for IT therapy to specialists in pain management is just the beginning. While patients typically return to the specialist for pump refills, it is important that they see their primary care physician regularly, as well. Vigilance is required of both the FP and the patient. Any sudden worsening in pain level or acute change in neurologic function must be reported to the pain specialist immediately. 

Adverse effects of medications are the most common complications

Kamran and Wright⁴³ performed a retrospective review of their practice’s Intrathecal Drug Delivery Systems database of 122 patients and found that adverse medication effects were most common, accounting for 77% of complications.

Catheter malfunctions were next, at 16%, followed by infections, at 5%.⁴³ In other studies, catheter-related complications were found to have an incidence of 15% to 25%.^44,45 Problems include kinking, breaking, leaking, and migration of the catheter. Advise patients to immediately contact their pain specialist for evaluation if they experience a sudden loss of, or change in, pain control.

Any sudden worsening in pain level or acute change in neurologic function must be reported immediately. Infectious complications, which occur infrequently, are usually limited to superficial wounds, although epidural abscesses and meningitis are possible.⁴⁶ Standard perioperative antibiotic administration helps to minimize the risk of infection. If a patient presents with signs and symptoms of an epidural abscess—back pain, fever, and variable neurologic deficits—emergent initiation of intravenous antibiotics is needed. Magnetic resonance imaging (MRI) with and without gadolinium should be obtained, as well.²²

Spinal damage. Although IT catheters are placed under fluoroscopic guidance, there is a risk of direct injury to the spinal cord; this is more common if the catheter is placed above the level of the conus medullaris. Damage to the spinal cord or exiting spinal nerves will manifest as pain, sensory loss, and/or weakness over a dermatomal distribution.⁴³

Neurologic sequelae, ranging from mild symptoms to paraplegia, can  result from the formation of a granuloma at the tip of the spinal catheter. A sudden increase in pain usually occurs prior to neurologic deterioration, thereby allowing for early detection and intervention.⁴⁷ Development of a granuloma appears to be related to the long-term infusion of high-concentration opioids.³⁴ The diagnosis is confirmed by MRI, but physical exam and history are imperative in making the initial diagnosis.

In cases of mild neurologic symptoms, a transition to saline infusion through the pump may allow the granuloma to absorb; more severe cases may require neurosurgical intervention.⁴⁷

Is your patient scheduled for an IT drug trial?

If a patient of yours is scheduled for an IT drug trial, ideally followed by pump implantation, microdosing—the practice of weaning the individual from oral opioids prior to the procedure so that very low doses of IT opioids will suffice—may play a role.^48,49 While this approach appears promising, however, there is little in the way of definitive evidence of efficacy.

CASE › Over time, Ms. G’s maintenance IT dose of morphine had to be slowly increased from 0.5 mg to 1 mg/d. At bimonthly visits with her FP, she consistently reports pain scores of 3 on a scale of 1 to 10. The patient’s function has returned to baseline, and she has minimal adverse effects. 

CORRESPONDENCE
Jessica Tsukanov, DO, Montefiore Medical Center, 3347 Steuben Avenue, Bronx, NY 10467; [email protected]

REFERENCES

1. Wang JK, Nauss LA, Thomas JE. Pain relief by intrathecally applied morphine in man. Anesthesiology. 1979;50:149-151.

2. Hayek SM, Hanes MC. Intrathecal therapy for chronic pain: current trends and future needs. Curr Pain Headache Rep. 2014;18:338.

3. Krames ES. Intraspinal opioid therapy for chronic nonmalignant pain: current practice and clinical guidelines. J Pain Symptom Manage. 1996;11:333-352.

4. Smith TJ, Staats PS, Deer T, et al; Implantable Drug Delivery Systems Study Group. Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: impact on pain, drug-related toxicity, and survival. J Clin Oncol. 2002;20:4040-4049.

5. Rauck RL, Cherry D, Boyer MF, et al. Long-term intrathecal opioid therapy with a patient-activated, implanted delivery system for the treatment of refractory cancer pain. J Pain. 2003;4:441-447.

6. Burton AW, Rajagopal A, Shah HN, et al. Epidural and intrathecal analgesia is effective in treating refractory cancer pain. Pain Med. 2004;5:239-247.

7. Hassenbusch SJ. Cost modeling for alternate routes of administration of opioids for cancer pain. Oncology. 1999;13(5 suppl 2):S63-S67.

8. Thimineur MA, Kravitz E, Vodapally MS. Intrathecal opioid treatment for chronic non-malignant pain: a 3-year prospective study. Pain. 2004;109:242-249.

9. Gerber HR. Intrathecal morphine for chronic benign pain. Best Pract Res Clin Anesthesiol. 2003;17:429-442.

10. Tuner JA, Sears JM, Loeser JD. Programmable intrathecal opioid delivery systems for chronic noncancer pain: a systematic review of effectiveness and complications. Clin J Pain. 2007;23:180-195.

11. Brown J, Klapow J, Doleys D, et al. Disease-specific and generic health outcomes: a model for the evaluation of long-term intrathecal opioid therapy in noncancer low back pain patients. Clin J Pain. 1999;15:122-131.

12. Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the Opioid Risk Tool. Pain Med. 2006;6:432-442.

13. Ahmed SU, Martin NM, Chang Y. Patient selection and trial methods for intraspinal drug delivery for chronic pain: a national survey. Neuromodulation. 2005;8:112-120.

14. Abs R, Verhelst J, Maeyaert J, et al. Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab. 2000;85:2215-2222.

15. Coffey RJ, Owens ML, Broste SK, et al. Mortality associated with implantation and management of intrathecal opioid drug infusion systems to treat noncancer pain. Anesthesiology. 2009;111:881-891.

16. Sjöberg M, Nitescu P, Appelgren L, et al. Long-term intrathecal morphine and bupivacaine in patients with refractory cancer pain. Results from a morphine:bupivacaine dose regimen of 0.5:4.75 mg/ml. Anesthesiology. 1994;80:284-297.

17. Sjöberg M, Appelgen L, Einarsson S, et al. Long-term intrathecal morphine and bupivacaine in “refractory” cancer pain. I. Results from the first series of 52 patients. Acta Anaesthsiol Scand. 1991;35:30-43.

18. Van Dongen RT, Crul BJ, De Bock M. Long-term intrathecal infusion of morphine and morphine/bupivacaine mixtures in the treatment of cancer pain: a retrospective analysis of 51 cases. Pain. 1993;55:119-123.

19. van Dongen RT, Crul BJ, van Egmond J. Intrathecal coadministration of bupivacaine diminishes morphine dose progression during long-term intrathecal infusion in cancer patients. Clin J Pain. 1999;15:166-172.

20. Deer TR, Caraway DL, Kim CK, et al. Clinical experience with intrathecal bupivacaine in combination with opioid for the treatment of chronic pain related to failed back surgery syndrome and metastatic cancer pain of the spine. Spine J. 2002;2:274-278.

21. Krames ES, Lanning RM. Intrathecal infusional analgesia for nonmalignant pain: analgesic efficacy of intrathecal opioid with or without bupivacaine. J Pain Symptom Manage. 1993;8:539-548.

22. Rainov NG, Heidecke V, Burkert W. Long-term intrathecal infusion of drug combinations for chronic back and leg pain. J Pain Symptom Manage. 2001;22:862-871.

23. Veizi IE, Hayek SM, Narouze S, et al. Combination of intrathecal opioids with bupivacaine attenuates opioid dose escalation in chronic noncancer pain patients. Pain Med. 2011;12:1481-1489.

24. Mironer YE, Haasis JC, Chapple I, et al. Efficacy and safety of intrathecal opioid/bupivacaine mixture in chronic nonmalignant pain: A double blind, randomized, crossover, multicenter study by the National Forum of Independent Pain Clinicians (NFIPC). Neuromodulation. 2002;5:208-213.

25. Staats PS, Yearwood T, Charapata SG, et al. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial. JAMA. 2004;291:63-70.

26. Rauck RL, Wallace MS, Leong MS, et al; Ziconotide 301 Study Group. A randomized, double-blind, placebo-controlled study of intrathecal ziconotide in adults with severe chronic pain. J Pain Symptom Manage. 2006;31:393-406.

27. Wallace MS, Rauck R, Fisher R, et al; Ziconotide 98-022 Study Group. Intrathecal ziconotide for severe chronic pain: safety and tolerability results of an open-label, long-term trial. Anesth Analg. 2008;106:628-637.

28. Maier C, Gockel HH, Gruhn K, et al. Increased risk of suicide under intrathecal ziconotide treatment? - a warning. Pain. 2011;152:235-237.

29. Ackerman LL, Follett KA, Rosenquist RW. Long-term outcomes during treatment of chronic pain with intrathecal clonidine or clonidine/opioid combinations. J Pain Symptom Manage. 2003;26:668-677.

30. Tarrico M, Adone R, Pagliacci C, et al. Pharmacological interventions for spasticity following spinal cord injury. Cochrane Database Syst Rev. 2000;(2):CD001131.

31. van Hilten BJ, van de Beek WT, Hoff JI, et al. Intrathecal baclofen for the treatment of dystonia in patients with reflex sympathetic dystrophy. N Engl J Med. 2000;343:625-630.

32. Herman RM, D’Luzansky SC, Ippolito R. Intrathecal baclofen suppresses central pain in patients with spinal lesions. A pilot study. Clin J Pain. 1992;8:338-345.

33. Deer T, Prager J, Levy R, et al. Polyanalgesic consensus conference 2012: recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel. Neuromodulation. 2012;15:436-466.

34. Yaksh TL, Coffey RJ. Spinal opiate toxicity. In: Proceedings of American Society of Regional Anesthesia and Pain Medication Conference; November 18-21, 2004; Phoenix, AZ.

35. Levy MH. Pharmacologic management of cancer pain. Semin Oncol. 1994;21:718-739.

36. Cousins MJ, Mather LE. Intrathecal and epidural administration of opioids. Anesthesiology. 1984;61:276-310.

37. Zeppetella G, O’Doherty CA, Collins S. Prevalence and characteristics of breakthrough pain in patients with non-malignant terminal disease admitted to a hospice. Palliat Med. 2001;15:243-246.

38. Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence and characteristics. Pain. 1990;41:273-281.

39. Hanks GW, Forbes K. Opioid responsiveness. Acta Anaesthesiol Scan. 1997;41:154-158.

40. Paice JA, Penn RD, Ryan WG. Altered sexual function and decreased testosterone in patients receiving intraspinal opioids. J Pain Symptom Manage. 1994;9:126-131.

41. Brennan MJ. The effect of opioid therapy on endocrine function. Am J Med. 2013;126(3 suppl 1):S12-S18.

42. Beard S, Hunn A. Wight J. Treatments for spasticity and pain in multiple sclerosis: a systematic review. Health Technol Assess. 2003;7:iii,ix-x,1-111.

43. Kamran S, Wright BD. Complications of intrathecal drug delivery systems. Neuromodulation. 2001;4:111-115.

44. Follett KA, Naumann CP. A prospective study of catheter-related complications of intrathecal drug delivery systems. J Pain Symptom Manage. 2000;19:209-215.

45. Follett KA, Burchiel K, Deer T, et al. Prevention of intrathecal drug delivery catheter-related complications. Neuromodulation. 2003;6:32-41.

46. Paice JA, Penn RD, Shott S. Intraspinal morphine for chronic pain: a retrospective, multicenter study. J Pain Symptom Manage. 1996;11:71-80.

47. Miele VJ, Price KO, Bloomfield S, et al. A review of intrathecal morphine therapy related granulomas. Eur J Pain. 2006;10:251-261.

48. Hayek SM. Intrathecal “microdosing”: reality or artifact? Pain Med. 2012;13:1664-1665.

49. Grider JS, Harned ME, Etscheidt MA. Patient selection and outcomes using a low-dose intrathecal opioid trialing method for chronic nonmalignant pain. Pain Physician. 2011;14:343-351.

A switch to hydromorphone 20 mg/d—the physician used the 5:1 morphine-to-hydromorphone conversion ratio, then decreased the dose by 50% to account for incomplete cross-tolerance—left Ms. G lethargic. In addition, her pain score rose to 5, and she began having difficulty swallowing the medication. Prior to the drug rotation, she was able to perform light tasks and was alert enough to interact with her family.

If Ms. G were your patient, what would be your next step?

By bypassing 
first-pass metabolism, intrathecal drug delivery provides greater pain relief at lower dosages and with fewer adverse effects than systemic delivery. Continuous intrathecal (IT) drug delivery systems have been in use for more than 30 years.¹ And, while IT administration of analgesia has become increasingly useful for patients with refractory chronic pain and spasticity, it remains an underutilized resource.² Delivered directly into the pre- and post-synaptic opioid receptors in the dorsal horn of the spinal cord, IT analgesia bypasses first-pass metabolism. The result: a higher rate of efficacy, with smaller dosages and fewer adverse effects than systemic delivery.¹

The drugs are delivered via a small battery-powered programmable pump that is implanted under the subcutaneous tissue of the abdomen and connected to a catheter tunneled to the site of spinal entry. The device must be refilled periodically—typically every one to 3 months—but this is not a difficult process. It can be done in an office setting or in the patient’s home by a specially trained visiting nurse.³

There is ample reason to consider this approach when systemic analgesics or antispasmodics fail to control pain or cause unacceptable adverse effects. So why isn’t it used more frequently? One factor may be that many primary care physicians—often the first practitioners called upon to manage these complicated cases—know too little about it.

Who is a potential candidate for IT analgesia? What medications can be administered via this route? What is the role of a family physician (FP) in coordinating and overseeing the care of a patient being treated with IT therapy? Our goals in writing this review are to address these questions.

Patient selection: Not just for cancer pain

Because of the invasive nature and high cost of implantation, intrathecal pumps are typically reserved for patients with a life expectancy of more than 6 months. FPs interested in referring patients for IT therapy have many factors to consider before consulting a pain specialist. Foremost among them are the different criteria for individuals with cancer-related pain and those with chronic nonmalignant pain.

IT analgesia for cancer pain has been shown to improve patients’ quality of life and potentially increase long-term survival due to a decrease in systemic toxicity.^4-6 An appropriate candidate is an individual who, like Ms. G, was initially responsive to systemic opioids but later developed refractory symptoms or intolerance.⁷ Because of the invasive nature and high cost of implantation, subcutaneous IT pumps are typically reserved for patients with a life expectancy of more than 6 months.⁷ But implantation may be considered for those with a shorter life expectancy if they have severe pain or cannot tolerate the adverse effects of systemic analgesia.

Noncancer pain is more complex

The use of IT analgesia in patients with chronic nonmalignant pain, such as failed back surgery syndrome, spasticity associated with multiple sclerosis, or diabetic neuropathy, is both more controversial and more complex. It is important for FPs to recognize the multidimensional nature of this type of pain, which may be complicated by physical, psychological, and behavioral factors, including the possibility of addiction.^8-11

Although IT analgesia is less subject to abuse and diversion than systemic opioids, the dependent relationship associated with a continuous delivery system makes risk stratification a necessity.¹² Psychological testing is commonly used to evaluate potential candidates for long-term IT analgesia.

Prior to placement, patients must have had a failed course of conservative pain management and have no surgical options, no medical contraindications (eg, spinal pathology or susceptibility to infection), and no evidence of active addiction.¹² A medication history is crucial, too, to identify use of anticoagulation therapy—a relative contraindication—as well as drug allergies and potential drug-drug interactions to guard against.³

An IT trial may be required

Psychological testing is commonly used to evaluate potential candidates for long-term intrathecal analgesia. It is common practice for patients to undergo an IT analgesia trial prior to implantation of a subcutaneous pump. This involves using an external pump to infuse the selected medication intrathecally and slowly titrating it according to symptoms for 2 to 3 days. During this time frame, the patient records his or her response; a reduction by more than half in VAS pain score is considered a success, indicating that the patient is an appropriate candidate for placement of the device.^3,13

Drug choices—a look at the evidence

The US Food and Drug Administration (FDA) has approved 3 medications for continuous IT delivery: morphine, ziconotide, and baclofen. But it is common practice to use alternative agents, such as other opioids, local anesthetics, or alpha 2-adrenergic agonists (TABLE).^3,14-34 

CASE  › Ms. G’s primary care physician referred her to a pain specialist, who thought she would benefit from IT analgesia. After a successful single-shot IT trial with 0.5 mg morphine, the patient underwent implantation.  The specialist chose morphine as the IT agent because of Ms. G’s history of successful pain relief with it, and because such a low dose was unlikely to be a problem for a patient with renal failure.

A month later, when she returned to the specialist to have the pump refilled, Ms. G reported a pain score of 3.

Opioids such as morphine exhibit a wider spread of analgesia when administered intrathecally, resulting in fewer adverse effects than systemic opioids.^13,35,36 The mu-opioid receptors in the dorsal horn of the spinal cord are the primary target of IT opioids.

In a multicenter randomized trial involving 200 cancer patients on opioids, Smith et al⁴ compared implantable IT drug delivery systems with comprehensive medical management. The mean VAS pain score in the IT group fell 52% vs a decline of 39% in the medical management group. 

The evidence supporting IT opioids for nonmalignant pain is not as strong. This may be due to inherent differences in pain mechanisms. In cancer pain, between 75% and 90% of pain is either nociceptive or mixed nociceptive-neuropathic; the etiology of noncancer pain is more variable.^37-39 

Although IT opioid therapy is associated with a lower incidence of adverse effects than systemic therapy, this route is not devoid of adverse effects. Opioids delivered intrathecally may still be associated with respiratory depression, constipation, urinary retention, nausea/vomiting, sweating, and hyperalgesia.³⁹ In addition, chronic opioid use suppresses the hypothalamic-pituitary-gonadal axis and the hypothalamic-pituitary-adrenal axis^14,40,41—a risk with long-term IT as well as systemic administration.¹⁴  Respiratory depression most commonly results from accidental overdosing, and patients must be monitored during initiation and dose escalation of IT opioid therapy.¹⁵

Local anesthetics. Numerous studies have documented the favorable outcomes of combining local anesthetics with opioids for patients with cancer^16-20 and noncancer pain.^21,22 Local anesthetics work via the blockade of voltage-gated sodium channels, interfering with neuron depolarization.¹⁷

Numerous studies have documented the favorable outcomes of combining local anesthetics with opioids for cancer and noncancer pain. A retrospective study in which patients with malignant pain and those with failed back surgery syndrome had bupivacaine added to their IT opioid solution found that the combination led to lower pain scores and a 23% reduction in opioid dosage.²⁰ In another retrospective review, researchers demonstrated that the coadministration of IT bupivacaine and an opioid decreased the rate of opioid dose escalation by 65% over the first year in patients with noncancer pain.²³

However, a double-blind randomized, crossover multicenter study found that in patients with chronic nonmalignant pain, the addition of bupivacaine to IT opioids failed to produce significant improvement in pain control compared with opioid use alone. Quality of life scores did improve, however, in the group receiving combination therapy.²⁴

Adverse effects of local anesthetics delivered intrathecally include numbness, paresthesias, weakness, bowel/bladder dysfunction, and neurotoxicity.^17,19,25  

Calcium channel blockers. Found in venom produced by the marine snail Conus magus, ziconotide blocks presynaptic N-type channels. It is the only calcium channel blocker used to manage chronic pain.²⁶ Several trials in patients with malignant and nonmalignant pain have shown a significant decrease in VAS pain scores compared with placebo.^25,26 In addition, a multicenter, double-blind placebo-controlled crossover study evaluating IT ziconotide for the treatment of refractory pain in 111 patients with cancer and AIDS found that the treatment group obtained significantly better pain relief than the controls (53% vs 17.5% using a VAS pain intensity score).²⁵ However, 31% of those in the treatment group experienced adverse effects, the most common of which were confusion, somnolence, and urinary retention.

Ziconotide has FDA approval only as monotherapy. But because of its high cost and adverse effect profile, it is mainly used in combination with other IT drugs.²⁷ Ziconotide increases the risk of suicide in patients with a history of depression.²⁸ The prevalence of adverse effects correlates with a higher dose, faster titration rate, and older age.^26,28

Alpha-2 adrenergic agonists. Clonidine is the only alpha-2 agonist with FDA approval for epidural use, with several studies supporting its off-label use in combination with IT therapy.^22,29 In a prospective open-label study evaluating combination IT therapy in patients with failed back surgery syndrome, 73% reported subjective ratings of good or excellent at 2-year follow-up.²² The most common adverse effects were sedation, hypotension, nausea, and dry mouth.

Gamma-aminobutyric acid (GABA) agonists. Baclofen, a GABA agonist with FDA approval for the treatment of spasticity, has been used intrathecally since the mid-1980s.³² Several studies have supported its effectiveness for this purpose.^30,42  Clinical studies have also found IT baclofen to be effective in treating conditions such as complex regional pain syndrome, central pain, and neuropathic pain secondary to failed back surgery syndrome.^31,32 In one randomized double-blind crossover trial, 7 women with complex regional pain syndrome were given bolus injections of baclofen or saline. Those treated with baclofen experienced a reduction in pain and regained function.³¹

In another trial—a double-blind placebo-controlled study of patients with multiple sclerosis and spinal cord injury comparing baclofen with placebo—those treated with baclofen showed significant reductions in dysesthetic and spasm-related pain.³² The most common adverse effects of baclofen are drowsiness, cognitive impairment, weakness, gastrointestinal complaints, and sexual dysfunction.³¹

Which patients and which drugs? An expert consensus

Due to the potential for inconsistent patient management and the use of therapies with anecdotal evidence, the Polyanalgesic Consensus Conference (PACC)—a panel of experts in IT therapy—convened in 2000, 2003, 2007, and 2011 to develop recommendations for IT therapy and an algorithm for drug selection. PACC’s list of chronic conditions for which IT should be considered includes axial low back pain, postherpetic neuralgia, spinal cord injury, spinal stenosis, pancreatitis, osteoporosis, compression fracture, and phantom limb pain, among others.

The algorithm contains separate arms for neuropathic, nociceptive, and mixed pain states. First-line agents for neuropathic pain include morphine, alone or combined with bupivacaine, and ziconotide. For nociceptive pain, morphine, hydromorphone, fentanyl, and ziconotide are all first-line agents; for mixed pain states, the appropriate choice should be based on the clinical scenario.³³

Overseeing IT pain management in primary care

Referring potential candidates for IT therapy to specialists in pain management is just the beginning. While patients typically return to the specialist for pump refills, it is important that they see their primary care physician regularly, as well. Vigilance is required of both the FP and the patient. Any sudden worsening in pain level or acute change in neurologic function must be reported to the pain specialist immediately. 

Adverse effects of medications are the most common complications

Kamran and Wright⁴³ performed a retrospective review of their practice’s Intrathecal Drug Delivery Systems database of 122 patients and found that adverse medication effects were most common, accounting for 77% of complications.

Catheter malfunctions were next, at 16%, followed by infections, at 5%.⁴³ In other studies, catheter-related complications were found to have an incidence of 15% to 25%.^44,45 Problems include kinking, breaking, leaking, and migration of the catheter. Advise patients to immediately contact their pain specialist for evaluation if they experience a sudden loss of, or change in, pain control.

Any sudden worsening in pain level or acute change in neurologic function must be reported immediately. Infectious complications, which occur infrequently, are usually limited to superficial wounds, although epidural abscesses and meningitis are possible.⁴⁶ Standard perioperative antibiotic administration helps to minimize the risk of infection. If a patient presents with signs and symptoms of an epidural abscess—back pain, fever, and variable neurologic deficits—emergent initiation of intravenous antibiotics is needed. Magnetic resonance imaging (MRI) with and without gadolinium should be obtained, as well.²²

Spinal damage. Although IT catheters are placed under fluoroscopic guidance, there is a risk of direct injury to the spinal cord; this is more common if the catheter is placed above the level of the conus medullaris. Damage to the spinal cord or exiting spinal nerves will manifest as pain, sensory loss, and/or weakness over a dermatomal distribution.⁴³

Neurologic sequelae, ranging from mild symptoms to paraplegia, can  result from the formation of a granuloma at the tip of the spinal catheter. A sudden increase in pain usually occurs prior to neurologic deterioration, thereby allowing for early detection and intervention.⁴⁷ Development of a granuloma appears to be related to the long-term infusion of high-concentration opioids.³⁴ The diagnosis is confirmed by MRI, but physical exam and history are imperative in making the initial diagnosis.

In cases of mild neurologic symptoms, a transition to saline infusion through the pump may allow the granuloma to absorb; more severe cases may require neurosurgical intervention.⁴⁷

Is your patient scheduled for an IT drug trial?

If a patient of yours is scheduled for an IT drug trial, ideally followed by pump implantation, microdosing—the practice of weaning the individual from oral opioids prior to the procedure so that very low doses of IT opioids will suffice—may play a role.^48,49 While this approach appears promising, however, there is little in the way of definitive evidence of efficacy.

CASE › Over time, Ms. G’s maintenance IT dose of morphine had to be slowly increased from 0.5 mg to 1 mg/d. At bimonthly visits with her FP, she consistently reports pain scores of 3 on a scale of 1 to 10. The patient’s function has returned to baseline, and she has minimal adverse effects. 

CORRESPONDENCE
Jessica Tsukanov, DO, Montefiore Medical Center, 3347 Steuben Avenue, Bronx, NY 10467; [email protected]

REFERENCES

1. Wang JK, Nauss LA, Thomas JE. Pain relief by intrathecally applied morphine in man. Anesthesiology. 1979;50:149-151.

2. Hayek SM, Hanes MC. Intrathecal therapy for chronic pain: current trends and future needs. Curr Pain Headache Rep. 2014;18:338.

3. Krames ES. Intraspinal opioid therapy for chronic nonmalignant pain: current practice and clinical guidelines. J Pain Symptom Manage. 1996;11:333-352.

4. Smith TJ, Staats PS, Deer T, et al; Implantable Drug Delivery Systems Study Group. Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: impact on pain, drug-related toxicity, and survival. J Clin Oncol. 2002;20:4040-4049.

5. Rauck RL, Cherry D, Boyer MF, et al. Long-term intrathecal opioid therapy with a patient-activated, implanted delivery system for the treatment of refractory cancer pain. J Pain. 2003;4:441-447.

6. Burton AW, Rajagopal A, Shah HN, et al. Epidural and intrathecal analgesia is effective in treating refractory cancer pain. Pain Med. 2004;5:239-247.

7. Hassenbusch SJ. Cost modeling for alternate routes of administration of opioids for cancer pain. Oncology. 1999;13(5 suppl 2):S63-S67.

8. Thimineur MA, Kravitz E, Vodapally MS. Intrathecal opioid treatment for chronic non-malignant pain: a 3-year prospective study. Pain. 2004;109:242-249.

9. Gerber HR. Intrathecal morphine for chronic benign pain. Best Pract Res Clin Anesthesiol. 2003;17:429-442.

10. Tuner JA, Sears JM, Loeser JD. Programmable intrathecal opioid delivery systems for chronic noncancer pain: a systematic review of effectiveness and complications. Clin J Pain. 2007;23:180-195.

11. Brown J, Klapow J, Doleys D, et al. Disease-specific and generic health outcomes: a model for the evaluation of long-term intrathecal opioid therapy in noncancer low back pain patients. Clin J Pain. 1999;15:122-131.

12. Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the Opioid Risk Tool. Pain Med. 2006;6:432-442.

13. Ahmed SU, Martin NM, Chang Y. Patient selection and trial methods for intraspinal drug delivery for chronic pain: a national survey. Neuromodulation. 2005;8:112-120.

14. Abs R, Verhelst J, Maeyaert J, et al. Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab. 2000;85:2215-2222.

15. Coffey RJ, Owens ML, Broste SK, et al. Mortality associated with implantation and management of intrathecal opioid drug infusion systems to treat noncancer pain. Anesthesiology. 2009;111:881-891.

16. Sjöberg M, Nitescu P, Appelgren L, et al. Long-term intrathecal morphine and bupivacaine in patients with refractory cancer pain. Results from a morphine:bupivacaine dose regimen of 0.5:4.75 mg/ml. Anesthesiology. 1994;80:284-297.

17. Sjöberg M, Appelgen L, Einarsson S, et al. Long-term intrathecal morphine and bupivacaine in “refractory” cancer pain. I. Results from the first series of 52 patients. Acta Anaesthsiol Scand. 1991;35:30-43.

18. Van Dongen RT, Crul BJ, De Bock M. Long-term intrathecal infusion of morphine and morphine/bupivacaine mixtures in the treatment of cancer pain: a retrospective analysis of 51 cases. Pain. 1993;55:119-123.

19. van Dongen RT, Crul BJ, van Egmond J. Intrathecal coadministration of bupivacaine diminishes morphine dose progression during long-term intrathecal infusion in cancer patients. Clin J Pain. 1999;15:166-172.

20. Deer TR, Caraway DL, Kim CK, et al. Clinical experience with intrathecal bupivacaine in combination with opioid for the treatment of chronic pain related to failed back surgery syndrome and metastatic cancer pain of the spine. Spine J. 2002;2:274-278.

21. Krames ES, Lanning RM. Intrathecal infusional analgesia for nonmalignant pain: analgesic efficacy of intrathecal opioid with or without bupivacaine. J Pain Symptom Manage. 1993;8:539-548.

22. Rainov NG, Heidecke V, Burkert W. Long-term intrathecal infusion of drug combinations for chronic back and leg pain. J Pain Symptom Manage. 2001;22:862-871.

23. Veizi IE, Hayek SM, Narouze S, et al. Combination of intrathecal opioids with bupivacaine attenuates opioid dose escalation in chronic noncancer pain patients. Pain Med. 2011;12:1481-1489.

24. Mironer YE, Haasis JC, Chapple I, et al. Efficacy and safety of intrathecal opioid/bupivacaine mixture in chronic nonmalignant pain: A double blind, randomized, crossover, multicenter study by the National Forum of Independent Pain Clinicians (NFIPC). Neuromodulation. 2002;5:208-213.

25. Staats PS, Yearwood T, Charapata SG, et al. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial. JAMA. 2004;291:63-70.

26. Rauck RL, Wallace MS, Leong MS, et al; Ziconotide 301 Study Group. A randomized, double-blind, placebo-controlled study of intrathecal ziconotide in adults with severe chronic pain. J Pain Symptom Manage. 2006;31:393-406.

27. Wallace MS, Rauck R, Fisher R, et al; Ziconotide 98-022 Study Group. Intrathecal ziconotide for severe chronic pain: safety and tolerability results of an open-label, long-term trial. Anesth Analg. 2008;106:628-637.

28. Maier C, Gockel HH, Gruhn K, et al. Increased risk of suicide under intrathecal ziconotide treatment? - a warning. Pain. 2011;152:235-237.

29. Ackerman LL, Follett KA, Rosenquist RW. Long-term outcomes during treatment of chronic pain with intrathecal clonidine or clonidine/opioid combinations. J Pain Symptom Manage. 2003;26:668-677.

30. Tarrico M, Adone R, Pagliacci C, et al. Pharmacological interventions for spasticity following spinal cord injury. Cochrane Database Syst Rev. 2000;(2):CD001131.

31. van Hilten BJ, van de Beek WT, Hoff JI, et al. Intrathecal baclofen for the treatment of dystonia in patients with reflex sympathetic dystrophy. N Engl J Med. 2000;343:625-630.

32. Herman RM, D’Luzansky SC, Ippolito R. Intrathecal baclofen suppresses central pain in patients with spinal lesions. A pilot study. Clin J Pain. 1992;8:338-345.

33. Deer T, Prager J, Levy R, et al. Polyanalgesic consensus conference 2012: recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel. Neuromodulation. 2012;15:436-466.

34. Yaksh TL, Coffey RJ. Spinal opiate toxicity. In: Proceedings of American Society of Regional Anesthesia and Pain Medication Conference; November 18-21, 2004; Phoenix, AZ.

35. Levy MH. Pharmacologic management of cancer pain. Semin Oncol. 1994;21:718-739.

36. Cousins MJ, Mather LE. Intrathecal and epidural administration of opioids. Anesthesiology. 1984;61:276-310.

37. Zeppetella G, O’Doherty CA, Collins S. Prevalence and characteristics of breakthrough pain in patients with non-malignant terminal disease admitted to a hospice. Palliat Med. 2001;15:243-246.

38. Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence and characteristics. Pain. 1990;41:273-281.

39. Hanks GW, Forbes K. Opioid responsiveness. Acta Anaesthesiol Scan. 1997;41:154-158.

40. Paice JA, Penn RD, Ryan WG. Altered sexual function and decreased testosterone in patients receiving intraspinal opioids. J Pain Symptom Manage. 1994;9:126-131.

41. Brennan MJ. The effect of opioid therapy on endocrine function. Am J Med. 2013;126(3 suppl 1):S12-S18.

42. Beard S, Hunn A. Wight J. Treatments for spasticity and pain in multiple sclerosis: a systematic review. Health Technol Assess. 2003;7:iii,ix-x,1-111.

43. Kamran S, Wright BD. Complications of intrathecal drug delivery systems. Neuromodulation. 2001;4:111-115.

44. Follett KA, Naumann CP. A prospective study of catheter-related complications of intrathecal drug delivery systems. J Pain Symptom Manage. 2000;19:209-215.

45. Follett KA, Burchiel K, Deer T, et al. Prevention of intrathecal drug delivery catheter-related complications. Neuromodulation. 2003;6:32-41.

46. Paice JA, Penn RD, Shott S. Intraspinal morphine for chronic pain: a retrospective, multicenter study. J Pain Symptom Manage. 1996;11:71-80.

47. Miele VJ, Price KO, Bloomfield S, et al. A review of intrathecal morphine therapy related granulomas. Eur J Pain. 2006;10:251-261.

48. Hayek SM. Intrathecal “microdosing”: reality or artifact? Pain Med. 2012;13:1664-1665.

49. Grider JS, Harned ME, Etscheidt MA. Patient selection and outcomes using a low-dose intrathecal opioid trialing method for chronic nonmalignant pain. Pain Physician. 2011;14:343-351.

A switch to hydromorphone 20 mg/d—the physician used the 5:1 morphine-to-hydromorphone conversion ratio, then decreased the dose by 50% to account for incomplete cross-tolerance—left Ms. G lethargic. In addition, her pain score rose to 5, and she began having difficulty swallowing the medication. Prior to the drug rotation, she was able to perform light tasks and was alert enough to interact with her family.

If Ms. G were your patient, what would be your next step?

By bypassing 
first-pass metabolism, intrathecal drug delivery provides greater pain relief at lower dosages and with fewer adverse effects than systemic delivery. Continuous intrathecal (IT) drug delivery systems have been in use for more than 30 years.¹ And, while IT administration of analgesia has become increasingly useful for patients with refractory chronic pain and spasticity, it remains an underutilized resource.² Delivered directly into the pre- and post-synaptic opioid receptors in the dorsal horn of the spinal cord, IT analgesia bypasses first-pass metabolism. The result: a higher rate of efficacy, with smaller dosages and fewer adverse effects than systemic delivery.¹

The drugs are delivered via a small battery-powered programmable pump that is implanted under the subcutaneous tissue of the abdomen and connected to a catheter tunneled to the site of spinal entry. The device must be refilled periodically—typically every one to 3 months—but this is not a difficult process. It can be done in an office setting or in the patient’s home by a specially trained visiting nurse.³

There is ample reason to consider this approach when systemic analgesics or antispasmodics fail to control pain or cause unacceptable adverse effects. So why isn’t it used more frequently? One factor may be that many primary care physicians—often the first practitioners called upon to manage these complicated cases—know too little about it.

Who is a potential candidate for IT analgesia? What medications can be administered via this route? What is the role of a family physician (FP) in coordinating and overseeing the care of a patient being treated with IT therapy? Our goals in writing this review are to address these questions.

Patient selection: Not just for cancer pain

Because of the invasive nature and high cost of implantation, intrathecal pumps are typically reserved for patients with a life expectancy of more than 6 months. FPs interested in referring patients for IT therapy have many factors to consider before consulting a pain specialist. Foremost among them are the different criteria for individuals with cancer-related pain and those with chronic nonmalignant pain.

IT analgesia for cancer pain has been shown to improve patients’ quality of life and potentially increase long-term survival due to a decrease in systemic toxicity.^4-6 An appropriate candidate is an individual who, like Ms. G, was initially responsive to systemic opioids but later developed refractory symptoms or intolerance.⁷ Because of the invasive nature and high cost of implantation, subcutaneous IT pumps are typically reserved for patients with a life expectancy of more than 6 months.⁷ But implantation may be considered for those with a shorter life expectancy if they have severe pain or cannot tolerate the adverse effects of systemic analgesia.

Noncancer pain is more complex

The use of IT analgesia in patients with chronic nonmalignant pain, such as failed back surgery syndrome, spasticity associated with multiple sclerosis, or diabetic neuropathy, is both more controversial and more complex. It is important for FPs to recognize the multidimensional nature of this type of pain, which may be complicated by physical, psychological, and behavioral factors, including the possibility of addiction.^8-11

Although IT analgesia is less subject to abuse and diversion than systemic opioids, the dependent relationship associated with a continuous delivery system makes risk stratification a necessity.¹² Psychological testing is commonly used to evaluate potential candidates for long-term IT analgesia.

Prior to placement, patients must have had a failed course of conservative pain management and have no surgical options, no medical contraindications (eg, spinal pathology or susceptibility to infection), and no evidence of active addiction.¹² A medication history is crucial, too, to identify use of anticoagulation therapy—a relative contraindication—as well as drug allergies and potential drug-drug interactions to guard against.³

An IT trial may be required

Psychological testing is commonly used to evaluate potential candidates for long-term intrathecal analgesia. It is common practice for patients to undergo an IT analgesia trial prior to implantation of a subcutaneous pump. This involves using an external pump to infuse the selected medication intrathecally and slowly titrating it according to symptoms for 2 to 3 days. During this time frame, the patient records his or her response; a reduction by more than half in VAS pain score is considered a success, indicating that the patient is an appropriate candidate for placement of the device.^3,13

Drug choices—a look at the evidence

The US Food and Drug Administration (FDA) has approved 3 medications for continuous IT delivery: morphine, ziconotide, and baclofen. But it is common practice to use alternative agents, such as other opioids, local anesthetics, or alpha 2-adrenergic agonists (TABLE).^3,14-34 

CASE  › Ms. G’s primary care physician referred her to a pain specialist, who thought she would benefit from IT analgesia. After a successful single-shot IT trial with 0.5 mg morphine, the patient underwent implantation.  The specialist chose morphine as the IT agent because of Ms. G’s history of successful pain relief with it, and because such a low dose was unlikely to be a problem for a patient with renal failure.

A month later, when she returned to the specialist to have the pump refilled, Ms. G reported a pain score of 3.

Opioids such as morphine exhibit a wider spread of analgesia when administered intrathecally, resulting in fewer adverse effects than systemic opioids.^13,35,36 The mu-opioid receptors in the dorsal horn of the spinal cord are the primary target of IT opioids.

In a multicenter randomized trial involving 200 cancer patients on opioids, Smith et al⁴ compared implantable IT drug delivery systems with comprehensive medical management. The mean VAS pain score in the IT group fell 52% vs a decline of 39% in the medical management group. 

The evidence supporting IT opioids for nonmalignant pain is not as strong. This may be due to inherent differences in pain mechanisms. In cancer pain, between 75% and 90% of pain is either nociceptive or mixed nociceptive-neuropathic; the etiology of noncancer pain is more variable.^37-39 

Although IT opioid therapy is associated with a lower incidence of adverse effects than systemic therapy, this route is not devoid of adverse effects. Opioids delivered intrathecally may still be associated with respiratory depression, constipation, urinary retention, nausea/vomiting, sweating, and hyperalgesia.³⁹ In addition, chronic opioid use suppresses the hypothalamic-pituitary-gonadal axis and the hypothalamic-pituitary-adrenal axis^14,40,41—a risk with long-term IT as well as systemic administration.¹⁴  Respiratory depression most commonly results from accidental overdosing, and patients must be monitored during initiation and dose escalation of IT opioid therapy.¹⁵

Local anesthetics. Numerous studies have documented the favorable outcomes of combining local anesthetics with opioids for patients with cancer^16-20 and noncancer pain.^21,22 Local anesthetics work via the blockade of voltage-gated sodium channels, interfering with neuron depolarization.¹⁷

Numerous studies have documented the favorable outcomes of combining local anesthetics with opioids for cancer and noncancer pain. A retrospective study in which patients with malignant pain and those with failed back surgery syndrome had bupivacaine added to their IT opioid solution found that the combination led to lower pain scores and a 23% reduction in opioid dosage.²⁰ In another retrospective review, researchers demonstrated that the coadministration of IT bupivacaine and an opioid decreased the rate of opioid dose escalation by 65% over the first year in patients with noncancer pain.²³

However, a double-blind randomized, crossover multicenter study found that in patients with chronic nonmalignant pain, the addition of bupivacaine to IT opioids failed to produce significant improvement in pain control compared with opioid use alone. Quality of life scores did improve, however, in the group receiving combination therapy.²⁴

Adverse effects of local anesthetics delivered intrathecally include numbness, paresthesias, weakness, bowel/bladder dysfunction, and neurotoxicity.^17,19,25  

Calcium channel blockers. Found in venom produced by the marine snail Conus magus, ziconotide blocks presynaptic N-type channels. It is the only calcium channel blocker used to manage chronic pain.²⁶ Several trials in patients with malignant and nonmalignant pain have shown a significant decrease in VAS pain scores compared with placebo.^25,26 In addition, a multicenter, double-blind placebo-controlled crossover study evaluating IT ziconotide for the treatment of refractory pain in 111 patients with cancer and AIDS found that the treatment group obtained significantly better pain relief than the controls (53% vs 17.5% using a VAS pain intensity score).²⁵ However, 31% of those in the treatment group experienced adverse effects, the most common of which were confusion, somnolence, and urinary retention.

Ziconotide has FDA approval only as monotherapy. But because of its high cost and adverse effect profile, it is mainly used in combination with other IT drugs.²⁷ Ziconotide increases the risk of suicide in patients with a history of depression.²⁸ The prevalence of adverse effects correlates with a higher dose, faster titration rate, and older age.^26,28

Alpha-2 adrenergic agonists. Clonidine is the only alpha-2 agonist with FDA approval for epidural use, with several studies supporting its off-label use in combination with IT therapy.^22,29 In a prospective open-label study evaluating combination IT therapy in patients with failed back surgery syndrome, 73% reported subjective ratings of good or excellent at 2-year follow-up.²² The most common adverse effects were sedation, hypotension, nausea, and dry mouth.

Gamma-aminobutyric acid (GABA) agonists. Baclofen, a GABA agonist with FDA approval for the treatment of spasticity, has been used intrathecally since the mid-1980s.³² Several studies have supported its effectiveness for this purpose.^30,42  Clinical studies have also found IT baclofen to be effective in treating conditions such as complex regional pain syndrome, central pain, and neuropathic pain secondary to failed back surgery syndrome.^31,32 In one randomized double-blind crossover trial, 7 women with complex regional pain syndrome were given bolus injections of baclofen or saline. Those treated with baclofen experienced a reduction in pain and regained function.³¹

In another trial—a double-blind placebo-controlled study of patients with multiple sclerosis and spinal cord injury comparing baclofen with placebo—those treated with baclofen showed significant reductions in dysesthetic and spasm-related pain.³² The most common adverse effects of baclofen are drowsiness, cognitive impairment, weakness, gastrointestinal complaints, and sexual dysfunction.³¹

Which patients and which drugs? An expert consensus

Due to the potential for inconsistent patient management and the use of therapies with anecdotal evidence, the Polyanalgesic Consensus Conference (PACC)—a panel of experts in IT therapy—convened in 2000, 2003, 2007, and 2011 to develop recommendations for IT therapy and an algorithm for drug selection. PACC’s list of chronic conditions for which IT should be considered includes axial low back pain, postherpetic neuralgia, spinal cord injury, spinal stenosis, pancreatitis, osteoporosis, compression fracture, and phantom limb pain, among others.

The algorithm contains separate arms for neuropathic, nociceptive, and mixed pain states. First-line agents for neuropathic pain include morphine, alone or combined with bupivacaine, and ziconotide. For nociceptive pain, morphine, hydromorphone, fentanyl, and ziconotide are all first-line agents; for mixed pain states, the appropriate choice should be based on the clinical scenario.³³

Overseeing IT pain management in primary care

Referring potential candidates for IT therapy to specialists in pain management is just the beginning. While patients typically return to the specialist for pump refills, it is important that they see their primary care physician regularly, as well. Vigilance is required of both the FP and the patient. Any sudden worsening in pain level or acute change in neurologic function must be reported to the pain specialist immediately. 

Adverse effects of medications are the most common complications

Kamran and Wright⁴³ performed a retrospective review of their practice’s Intrathecal Drug Delivery Systems database of 122 patients and found that adverse medication effects were most common, accounting for 77% of complications.

Catheter malfunctions were next, at 16%, followed by infections, at 5%.⁴³ In other studies, catheter-related complications were found to have an incidence of 15% to 25%.^44,45 Problems include kinking, breaking, leaking, and migration of the catheter. Advise patients to immediately contact their pain specialist for evaluation if they experience a sudden loss of, or change in, pain control.

Any sudden worsening in pain level or acute change in neurologic function must be reported immediately. Infectious complications, which occur infrequently, are usually limited to superficial wounds, although epidural abscesses and meningitis are possible.⁴⁶ Standard perioperative antibiotic administration helps to minimize the risk of infection. If a patient presents with signs and symptoms of an epidural abscess—back pain, fever, and variable neurologic deficits—emergent initiation of intravenous antibiotics is needed. Magnetic resonance imaging (MRI) with and without gadolinium should be obtained, as well.²²

Spinal damage. Although IT catheters are placed under fluoroscopic guidance, there is a risk of direct injury to the spinal cord; this is more common if the catheter is placed above the level of the conus medullaris. Damage to the spinal cord or exiting spinal nerves will manifest as pain, sensory loss, and/or weakness over a dermatomal distribution.⁴³

Neurologic sequelae, ranging from mild symptoms to paraplegia, can  result from the formation of a granuloma at the tip of the spinal catheter. A sudden increase in pain usually occurs prior to neurologic deterioration, thereby allowing for early detection and intervention.⁴⁷ Development of a granuloma appears to be related to the long-term infusion of high-concentration opioids.³⁴ The diagnosis is confirmed by MRI, but physical exam and history are imperative in making the initial diagnosis.

In cases of mild neurologic symptoms, a transition to saline infusion through the pump may allow the granuloma to absorb; more severe cases may require neurosurgical intervention.⁴⁷

Is your patient scheduled for an IT drug trial?

If a patient of yours is scheduled for an IT drug trial, ideally followed by pump implantation, microdosing—the practice of weaning the individual from oral opioids prior to the procedure so that very low doses of IT opioids will suffice—may play a role.^48,49 While this approach appears promising, however, there is little in the way of definitive evidence of efficacy.

CASE › Over time, Ms. G’s maintenance IT dose of morphine had to be slowly increased from 0.5 mg to 1 mg/d. At bimonthly visits with her FP, she consistently reports pain scores of 3 on a scale of 1 to 10. The patient’s function has returned to baseline, and she has minimal adverse effects. 

CORRESPONDENCE
Jessica Tsukanov, DO, Montefiore Medical Center, 3347 Steuben Avenue, Bronx, NY 10467; [email protected]

REFERENCES

1. Wang JK, Nauss LA, Thomas JE. Pain relief by intrathecally applied morphine in man. Anesthesiology. 1979;50:149-151.

2. Hayek SM, Hanes MC. Intrathecal therapy for chronic pain: current trends and future needs. Curr Pain Headache Rep. 2014;18:338.

3. Krames ES. Intraspinal opioid therapy for chronic nonmalignant pain: current practice and clinical guidelines. J Pain Symptom Manage. 1996;11:333-352.

4. Smith TJ, Staats PS, Deer T, et al; Implantable Drug Delivery Systems Study Group. Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: impact on pain, drug-related toxicity, and survival. J Clin Oncol. 2002;20:4040-4049.

5. Rauck RL, Cherry D, Boyer MF, et al. Long-term intrathecal opioid therapy with a patient-activated, implanted delivery system for the treatment of refractory cancer pain. J Pain. 2003;4:441-447.

6. Burton AW, Rajagopal A, Shah HN, et al. Epidural and intrathecal analgesia is effective in treating refractory cancer pain. Pain Med. 2004;5:239-247.

7. Hassenbusch SJ. Cost modeling for alternate routes of administration of opioids for cancer pain. Oncology. 1999;13(5 suppl 2):S63-S67.

8. Thimineur MA, Kravitz E, Vodapally MS. Intrathecal opioid treatment for chronic non-malignant pain: a 3-year prospective study. Pain. 2004;109:242-249.

9. Gerber HR. Intrathecal morphine for chronic benign pain. Best Pract Res Clin Anesthesiol. 2003;17:429-442.

10. Tuner JA, Sears JM, Loeser JD. Programmable intrathecal opioid delivery systems for chronic noncancer pain: a systematic review of effectiveness and complications. Clin J Pain. 2007;23:180-195.

11. Brown J, Klapow J, Doleys D, et al. Disease-specific and generic health outcomes: a model for the evaluation of long-term intrathecal opioid therapy in noncancer low back pain patients. Clin J Pain. 1999;15:122-131.

12. Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the Opioid Risk Tool. Pain Med. 2006;6:432-442.

13. Ahmed SU, Martin NM, Chang Y. Patient selection and trial methods for intraspinal drug delivery for chronic pain: a national survey. Neuromodulation. 2005;8:112-120.

14. Abs R, Verhelst J, Maeyaert J, et al. Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab. 2000;85:2215-2222.

15. Coffey RJ, Owens ML, Broste SK, et al. Mortality associated with implantation and management of intrathecal opioid drug infusion systems to treat noncancer pain. Anesthesiology. 2009;111:881-891.

16. Sjöberg M, Nitescu P, Appelgren L, et al. Long-term intrathecal morphine and bupivacaine in patients with refractory cancer pain. Results from a morphine:bupivacaine dose regimen of 0.5:4.75 mg/ml. Anesthesiology. 1994;80:284-297.

17. Sjöberg M, Appelgen L, Einarsson S, et al. Long-term intrathecal morphine and bupivacaine in “refractory” cancer pain. I. Results from the first series of 52 patients. Acta Anaesthsiol Scand. 1991;35:30-43.

18. Van Dongen RT, Crul BJ, De Bock M. Long-term intrathecal infusion of morphine and morphine/bupivacaine mixtures in the treatment of cancer pain: a retrospective analysis of 51 cases. Pain. 1993;55:119-123.

19. van Dongen RT, Crul BJ, van Egmond J. Intrathecal coadministration of bupivacaine diminishes morphine dose progression during long-term intrathecal infusion in cancer patients. Clin J Pain. 1999;15:166-172.

20. Deer TR, Caraway DL, Kim CK, et al. Clinical experience with intrathecal bupivacaine in combination with opioid for the treatment of chronic pain related to failed back surgery syndrome and metastatic cancer pain of the spine. Spine J. 2002;2:274-278.

21. Krames ES, Lanning RM. Intrathecal infusional analgesia for nonmalignant pain: analgesic efficacy of intrathecal opioid with or without bupivacaine. J Pain Symptom Manage. 1993;8:539-548.

22. Rainov NG, Heidecke V, Burkert W. Long-term intrathecal infusion of drug combinations for chronic back and leg pain. J Pain Symptom Manage. 2001;22:862-871.

23. Veizi IE, Hayek SM, Narouze S, et al. Combination of intrathecal opioids with bupivacaine attenuates opioid dose escalation in chronic noncancer pain patients. Pain Med. 2011;12:1481-1489.

24. Mironer YE, Haasis JC, Chapple I, et al. Efficacy and safety of intrathecal opioid/bupivacaine mixture in chronic nonmalignant pain: A double blind, randomized, crossover, multicenter study by the National Forum of Independent Pain Clinicians (NFIPC). Neuromodulation. 2002;5:208-213.

25. Staats PS, Yearwood T, Charapata SG, et al. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial. JAMA. 2004;291:63-70.

26. Rauck RL, Wallace MS, Leong MS, et al; Ziconotide 301 Study Group. A randomized, double-blind, placebo-controlled study of intrathecal ziconotide in adults with severe chronic pain. J Pain Symptom Manage. 2006;31:393-406.

27. Wallace MS, Rauck R, Fisher R, et al; Ziconotide 98-022 Study Group. Intrathecal ziconotide for severe chronic pain: safety and tolerability results of an open-label, long-term trial. Anesth Analg. 2008;106:628-637.

28. Maier C, Gockel HH, Gruhn K, et al. Increased risk of suicide under intrathecal ziconotide treatment? - a warning. Pain. 2011;152:235-237.

29. Ackerman LL, Follett KA, Rosenquist RW. Long-term outcomes during treatment of chronic pain with intrathecal clonidine or clonidine/opioid combinations. J Pain Symptom Manage. 2003;26:668-677.

30. Tarrico M, Adone R, Pagliacci C, et al. Pharmacological interventions for spasticity following spinal cord injury. Cochrane Database Syst Rev. 2000;(2):CD001131.

31. van Hilten BJ, van de Beek WT, Hoff JI, et al. Intrathecal baclofen for the treatment of dystonia in patients with reflex sympathetic dystrophy. N Engl J Med. 2000;343:625-630.

32. Herman RM, D’Luzansky SC, Ippolito R. Intrathecal baclofen suppresses central pain in patients with spinal lesions. A pilot study. Clin J Pain. 1992;8:338-345.

33. Deer T, Prager J, Levy R, et al. Polyanalgesic consensus conference 2012: recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel. Neuromodulation. 2012;15:436-466.

34. Yaksh TL, Coffey RJ. Spinal opiate toxicity. In: Proceedings of American Society of Regional Anesthesia and Pain Medication Conference; November 18-21, 2004; Phoenix, AZ.

35. Levy MH. Pharmacologic management of cancer pain. Semin Oncol. 1994;21:718-739.

36. Cousins MJ, Mather LE. Intrathecal and epidural administration of opioids. Anesthesiology. 1984;61:276-310.

37. Zeppetella G, O’Doherty CA, Collins S. Prevalence and characteristics of breakthrough pain in patients with non-malignant terminal disease admitted to a hospice. Palliat Med. 2001;15:243-246.

38. Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence and characteristics. Pain. 1990;41:273-281.

39. Hanks GW, Forbes K. Opioid responsiveness. Acta Anaesthesiol Scan. 1997;41:154-158.

40. Paice JA, Penn RD, Ryan WG. Altered sexual function and decreased testosterone in patients receiving intraspinal opioids. J Pain Symptom Manage. 1994;9:126-131.

41. Brennan MJ. The effect of opioid therapy on endocrine function. Am J Med. 2013;126(3 suppl 1):S12-S18.

42. Beard S, Hunn A. Wight J. Treatments for spasticity and pain in multiple sclerosis: a systematic review. Health Technol Assess. 2003;7:iii,ix-x,1-111.

43. Kamran S, Wright BD. Complications of intrathecal drug delivery systems. Neuromodulation. 2001;4:111-115.

44. Follett KA, Naumann CP. A prospective study of catheter-related complications of intrathecal drug delivery systems. J Pain Symptom Manage. 2000;19:209-215.

45. Follett KA, Burchiel K, Deer T, et al. Prevention of intrathecal drug delivery catheter-related complications. Neuromodulation. 2003;6:32-41.

46. Paice JA, Penn RD, Shott S. Intraspinal morphine for chronic pain: a retrospective, multicenter study. J Pain Symptom Manage. 1996;11:71-80.

47. Miele VJ, Price KO, Bloomfield S, et al. A review of intrathecal morphine therapy related granulomas. Eur J Pain. 2006;10:251-261.

48. Hayek SM. Intrathecal “microdosing”: reality or artifact? Pain Med. 2012;13:1664-1665.

49. Grider JS, Harned ME, Etscheidt MA. Patient selection and outcomes using a low-dose intrathecal opioid trialing method for chronic nonmalignant pain. Pain Physician. 2011;14:343-351.

Emergency physicians routinely perform sign-outs (also referred to as handoffs and handovers) at shift changes and during consultations. Despite their frequency, however, sign-outs continue to be cited as a significant source of medical error in the ED.¹

Sign-outs should take place in a quiet area of the hospital, with no distractions, and should allot sufficient time to discuss pertinent aspects of patient care. Unfortunately, this ideal handover process is particularly difficult to achieve in the ED.^2-4 Moreover, to date, only a few sign-out studies have evaluated empirical evidence for improved patient care.5

Formal Instruction

Despite multiple studies supporting the implementation of a standardized sign-out process,^1,6,7 a 2013 study by Kessler et al⁴ showed that only 10.9% of US emergency medicine (EM) residents reported receiving hand-off education.⁴ This number is consistent with the 93.9% of EM program directors who stated that assessments of hand-off proficiencies were not conducted in their US programs.⁴

In a survey conducted by Sinha et al, ⁸ only 25.6% of EM residency and pediatric EM fellowship directors reported any formal instruction on sign-outs—even though handoff education is a required component of resident patient safety education in the Clinical Learning Environment Review Program sponsored by the Accreditation Council for Graduate Medical Education in 2011.⁹

A stronger foundation in quality sign-outs during residency will likely enhance patient care. For example, Horwitz et al¹⁰ showed that 29% of house staff had a patient who experienced an adverse event after an ED-to-inpatient transfer. Contributing factors, including inaccurate or incomplete information, can potentially be corrected with a better sign-out process. ¹⁰

Sign-Out Tools

To improve the sign-out process and patient outcomes and experiences, one of the recommendations from the 2012 American College of Emergency Physicians (ACEP) Transitions of Care Task Force Report calls for collaboration with the Society of Hospitalist Medicine to hardwire a process between the EP and hospitalist.¹¹ Since this report, several sign-out materials have become available and are accessible from various organizations. The Table highlights a list of sign-out methods applicable to the ED as well as other hospital departments.

Safer Sign-Out Tool Kit

The most publicized ED tool is Safer Sign Out from the Emergency Medicine Patient Safety Foundation (EMPSF), a third-party nonprofit organization founded in 2003.12 Safer Sign Out focuses on using a physical checklist, dedicated time to sign-out, bidirectional communication, and confirmation of the sign-out with staff. The EMPSF provides all of the necessities to implement their sign-out tool department-wide, including training videos and pre- and postsurveys, in addition to the tool itself. The kit costs $1,695 to implement at a single site.¹² Although widely publicized, this toolkit has not yet been externally validated in the peer-reviewed literature.

Sign-Out Checklist

On a smaller scale, Dubosh et al¹³ recently found success using a sign-out checklist with residents in the ED at a single institution (See Box). The components of their checklist included history of present illness (HPI), ED course, pending studies, likely disposition, possible issues, and algorithms for disposition. In this study, trained research assistants monitored the sign-outs before and after implementation of the checklist. There were statistically significant improvements in the areas of HPI, ED course, possible diagnosis, and team awareness of the treatment plan. Of note, there was no difference in the amount of time required for sign-out with and without the checklist (1.42 vs 1.39 minutes, respectively).¹³ (See the Box for a convenient pocket-sized reproduction of the sign-out tool.)

ABC of Handover Tool

Developed in the United Kingdom, the ABC of Handover tool was specifically designed for use in the ED. This tool focuses on departmental awareness prior to specific patient sign-outs. The full-sheet paper checklist includes bed allocations in the ED and the hospital; available colleagues and consultants; a list of any deaths or dangerously ill patients; and equipment review. .¹⁴ The ABC of Handover tool is essentially a preamble to patient specifics compiled by surveying ED staff and attending physicians at a single urban center. It has not yet been validated in the peer-reviewed literature.¹⁴

ACEP Recommendations

Although ACEP does not endorse a particular sign-out tool,¹¹ its Section of Quality Improvement and Patient Safety created a framework of ED sign-outs and recommendations in which EPs should adhere to the following protocol:

• Limit unnecessary patient handoffs;
• Limit interruptions and distractions during sign-out;
• Provide a succinct overview; </lli>
• Highlight remaining tasks, plans, and possible changes for each patient;
• Have laboratory and imaging studies available during sign-out;
• Encourage bidirectional discourse about the assessments and treatment plans;
• Account for all patients; and
• Clearly signal the moment of full-care transfer.

I-PASS Handoff System

The I-PASS Handoff System is a landmark multicenter pediatric intervention largely funded by the US Department of Health and Human Services. The mnemonic I-PASS stands for the following:

• Illness severity;
• Patient summary;
• Action items;
• Situation awareness and contingency planning; and
• Synthesis by the receiver.

This system is part of a complete curriculum for pediatrics residents published in 2014.¹⁵ Single-center prospective validation found a 45.9% relative risk reduction in preventable medical errors without an increase in verbal sign-out length (32.3 minutes before the intervention vs 33.3 minutes after the intervention).⁶ This was confirmed in a multicenter prospective validation that found a 23% relative reduction in preventable medical errors—also without a change in sign-out length with versus without the tool (2.4 minutes vs 2.5 minutes, respectively).¹⁶ The bundle and curriculum are available for free and may be accessed online.¹⁵

SBAR Tool

The Situation, Background, Assessment, and Recommendation (SBAR) is the time-honored tool most well known in nursing—one that is of benefit to physicians as well.¹⁷ In one study, SBAR demonstrated a reduction in unexpected deaths hospital-wide at a single institution when nurses used it to communicate with physicians.¹⁸ Additional support, however, is largely based on nurse and physician perception of improved communication and more thorough handoffs.^19,20

Format and Outcomes

The format of a sign-out does not appear to influence outcomes, though acronyms and mnemonics appear effective—eg, I-PASS,¹⁶ SBAR,¹⁷ and IMOUTA²¹ (an otolaryngology resident tool that stands for identifying data, medical course, outcomes possible tonight, and responsibilities to do tonight). Riesenberg et al⁵ provide an overview of 24 different mnemonics described in the handoff literature.

In addition to mnemonic tools, paper pocket cards²² and electronic medical record prompts¹³ also appear effective. Regardless of which tool is employed, the common theme is practice standardization with dedicated time for open commun¬ication.

Practical Challenges

Aside from standardization, there are numerous other factors that can lead to a poor sign-out experience in the ED. These include a loud and disruptive background; the uncertainty of who the charge physician is post-sign-out when both are still physically present; lack of “red flags” that help identify dangerous hand-offs; the goal to be concise; and the economic structure of the physician group.^1,5 These systems issues each need to be addressed; however, a standardized hand-off can decrease the margin of error and is relatively easy to implement.

Conclusion

Sign-outs are central to patient care, especially in the ED. Achieving the most effective sign-outs possible is of paramount importance and is deeply supported by respected physician groups.^11,12,17,23 Several ED-specific standardized sign-outs exist with varying emphases and empirical support. The method with the most empirical support is the pediatrics initiative, I-PASS, and is one that should be considered by EPs and departments when selecting a standardized method. Even if a department is not adopting a particular method, individual clinicians can implement a standardized sign-out in their own daily practice—beginning with the next shift. A safe and effective sign-out in a reasonable timeframe in a busy ED is not only possible, but imperative.

Dr Phillips is a senior resident in the Stanford/Kaiser Emergency Medicine Residency, Stanford University School of Medicine, California. Mr Malamet is a fourth-year medical student at Philadelphia College of Osteopathic Medicine, Pennsylvania. Dr Williams is the associate program director for the Stanford/Kaiser Emergency Medicine Residency and a clinical associate professor, Surgery - Emergency Medicine at Stanford University School of Medicine, California.

Disclosure Statement: The authors express no conflicts of interest. The views expressed in this article are those of the author and do not represent the official position of the US Air Force, Department of Defense, or US Government.

Emergency physicians routinely perform sign-outs (also referred to as handoffs and handovers) at shift changes and during consultations. Despite their frequency, however, sign-outs continue to be cited as a significant source of medical error in the ED.¹

Sign-outs should take place in a quiet area of the hospital, with no distractions, and should allot sufficient time to discuss pertinent aspects of patient care. Unfortunately, this ideal handover process is particularly difficult to achieve in the ED.^2-4 Moreover, to date, only a few sign-out studies have evaluated empirical evidence for improved patient care.5

Formal Instruction

Despite multiple studies supporting the implementation of a standardized sign-out process,^1,6,7 a 2013 study by Kessler et al⁴ showed that only 10.9% of US emergency medicine (EM) residents reported receiving hand-off education.⁴ This number is consistent with the 93.9% of EM program directors who stated that assessments of hand-off proficiencies were not conducted in their US programs.⁴

In a survey conducted by Sinha et al, ⁸ only 25.6% of EM residency and pediatric EM fellowship directors reported any formal instruction on sign-outs—even though handoff education is a required component of resident patient safety education in the Clinical Learning Environment Review Program sponsored by the Accreditation Council for Graduate Medical Education in 2011.⁹

A stronger foundation in quality sign-outs during residency will likely enhance patient care. For example, Horwitz et al¹⁰ showed that 29% of house staff had a patient who experienced an adverse event after an ED-to-inpatient transfer. Contributing factors, including inaccurate or incomplete information, can potentially be corrected with a better sign-out process. ¹⁰

Sign-Out Tools

To improve the sign-out process and patient outcomes and experiences, one of the recommendations from the 2012 American College of Emergency Physicians (ACEP) Transitions of Care Task Force Report calls for collaboration with the Society of Hospitalist Medicine to hardwire a process between the EP and hospitalist.¹¹ Since this report, several sign-out materials have become available and are accessible from various organizations. The Table highlights a list of sign-out methods applicable to the ED as well as other hospital departments.

Safer Sign-Out Tool Kit

The most publicized ED tool is Safer Sign Out from the Emergency Medicine Patient Safety Foundation (EMPSF), a third-party nonprofit organization founded in 2003.12 Safer Sign Out focuses on using a physical checklist, dedicated time to sign-out, bidirectional communication, and confirmation of the sign-out with staff. The EMPSF provides all of the necessities to implement their sign-out tool department-wide, including training videos and pre- and postsurveys, in addition to the tool itself. The kit costs $1,695 to implement at a single site.¹² Although widely publicized, this toolkit has not yet been externally validated in the peer-reviewed literature.

Sign-Out Checklist

On a smaller scale, Dubosh et al¹³ recently found success using a sign-out checklist with residents in the ED at a single institution (See Box). The components of their checklist included history of present illness (HPI), ED course, pending studies, likely disposition, possible issues, and algorithms for disposition. In this study, trained research assistants monitored the sign-outs before and after implementation of the checklist. There were statistically significant improvements in the areas of HPI, ED course, possible diagnosis, and team awareness of the treatment plan. Of note, there was no difference in the amount of time required for sign-out with and without the checklist (1.42 vs 1.39 minutes, respectively).¹³ (See the Box for a convenient pocket-sized reproduction of the sign-out tool.)

ABC of Handover Tool

Developed in the United Kingdom, the ABC of Handover tool was specifically designed for use in the ED. This tool focuses on departmental awareness prior to specific patient sign-outs. The full-sheet paper checklist includes bed allocations in the ED and the hospital; available colleagues and consultants; a list of any deaths or dangerously ill patients; and equipment review. .¹⁴ The ABC of Handover tool is essentially a preamble to patient specifics compiled by surveying ED staff and attending physicians at a single urban center. It has not yet been validated in the peer-reviewed literature.¹⁴

ACEP Recommendations

Although ACEP does not endorse a particular sign-out tool,¹¹ its Section of Quality Improvement and Patient Safety created a framework of ED sign-outs and recommendations in which EPs should adhere to the following protocol:

• Limit unnecessary patient handoffs;
• Limit interruptions and distractions during sign-out;
• Provide a succinct overview; </lli>
• Highlight remaining tasks, plans, and possible changes for each patient;
• Have laboratory and imaging studies available during sign-out;
• Encourage bidirectional discourse about the assessments and treatment plans;
• Account for all patients; and
• Clearly signal the moment of full-care transfer.

I-PASS Handoff System

The I-PASS Handoff System is a landmark multicenter pediatric intervention largely funded by the US Department of Health and Human Services. The mnemonic I-PASS stands for the following:

• Illness severity;
• Patient summary;
• Action items;
• Situation awareness and contingency planning; and
• Synthesis by the receiver.

This system is part of a complete curriculum for pediatrics residents published in 2014.¹⁵ Single-center prospective validation found a 45.9% relative risk reduction in preventable medical errors without an increase in verbal sign-out length (32.3 minutes before the intervention vs 33.3 minutes after the intervention).⁶ This was confirmed in a multicenter prospective validation that found a 23% relative reduction in preventable medical errors—also without a change in sign-out length with versus without the tool (2.4 minutes vs 2.5 minutes, respectively).¹⁶ The bundle and curriculum are available for free and may be accessed online.¹⁵

SBAR Tool

The Situation, Background, Assessment, and Recommendation (SBAR) is the time-honored tool most well known in nursing—one that is of benefit to physicians as well.¹⁷ In one study, SBAR demonstrated a reduction in unexpected deaths hospital-wide at a single institution when nurses used it to communicate with physicians.¹⁸ Additional support, however, is largely based on nurse and physician perception of improved communication and more thorough handoffs.^19,20

Format and Outcomes

The format of a sign-out does not appear to influence outcomes, though acronyms and mnemonics appear effective—eg, I-PASS,¹⁶ SBAR,¹⁷ and IMOUTA²¹ (an otolaryngology resident tool that stands for identifying data, medical course, outcomes possible tonight, and responsibilities to do tonight). Riesenberg et al⁵ provide an overview of 24 different mnemonics described in the handoff literature.

In addition to mnemonic tools, paper pocket cards²² and electronic medical record prompts¹³ also appear effective. Regardless of which tool is employed, the common theme is practice standardization with dedicated time for open commun¬ication.

Practical Challenges

Aside from standardization, there are numerous other factors that can lead to a poor sign-out experience in the ED. These include a loud and disruptive background; the uncertainty of who the charge physician is post-sign-out when both are still physically present; lack of “red flags” that help identify dangerous hand-offs; the goal to be concise; and the economic structure of the physician group.^1,5 These systems issues each need to be addressed; however, a standardized hand-off can decrease the margin of error and is relatively easy to implement.

Conclusion

Sign-outs are central to patient care, especially in the ED. Achieving the most effective sign-outs possible is of paramount importance and is deeply supported by respected physician groups.^11,12,17,23 Several ED-specific standardized sign-outs exist with varying emphases and empirical support. The method with the most empirical support is the pediatrics initiative, I-PASS, and is one that should be considered by EPs and departments when selecting a standardized method. Even if a department is not adopting a particular method, individual clinicians can implement a standardized sign-out in their own daily practice—beginning with the next shift. A safe and effective sign-out in a reasonable timeframe in a busy ED is not only possible, but imperative.

Dr Phillips is a senior resident in the Stanford/Kaiser Emergency Medicine Residency, Stanford University School of Medicine, California. Mr Malamet is a fourth-year medical student at Philadelphia College of Osteopathic Medicine, Pennsylvania. Dr Williams is the associate program director for the Stanford/Kaiser Emergency Medicine Residency and a clinical associate professor, Surgery - Emergency Medicine at Stanford University School of Medicine, California.

Disclosure Statement: The authors express no conflicts of interest. The views expressed in this article are those of the author and do not represent the official position of the US Air Force, Department of Defense, or US Government.

Emergency physicians routinely perform sign-outs (also referred to as handoffs and handovers) at shift changes and during consultations. Despite their frequency, however, sign-outs continue to be cited as a significant source of medical error in the ED.¹

Sign-outs should take place in a quiet area of the hospital, with no distractions, and should allot sufficient time to discuss pertinent aspects of patient care. Unfortunately, this ideal handover process is particularly difficult to achieve in the ED.^2-4 Moreover, to date, only a few sign-out studies have evaluated empirical evidence for improved patient care.5

Formal Instruction

Despite multiple studies supporting the implementation of a standardized sign-out process,^1,6,7 a 2013 study by Kessler et al⁴ showed that only 10.9% of US emergency medicine (EM) residents reported receiving hand-off education.⁴ This number is consistent with the 93.9% of EM program directors who stated that assessments of hand-off proficiencies were not conducted in their US programs.⁴

In a survey conducted by Sinha et al, ⁸ only 25.6% of EM residency and pediatric EM fellowship directors reported any formal instruction on sign-outs—even though handoff education is a required component of resident patient safety education in the Clinical Learning Environment Review Program sponsored by the Accreditation Council for Graduate Medical Education in 2011.⁹

A stronger foundation in quality sign-outs during residency will likely enhance patient care. For example, Horwitz et al¹⁰ showed that 29% of house staff had a patient who experienced an adverse event after an ED-to-inpatient transfer. Contributing factors, including inaccurate or incomplete information, can potentially be corrected with a better sign-out process. ¹⁰

Sign-Out Tools

To improve the sign-out process and patient outcomes and experiences, one of the recommendations from the 2012 American College of Emergency Physicians (ACEP) Transitions of Care Task Force Report calls for collaboration with the Society of Hospitalist Medicine to hardwire a process between the EP and hospitalist.¹¹ Since this report, several sign-out materials have become available and are accessible from various organizations. The Table highlights a list of sign-out methods applicable to the ED as well as other hospital departments.

Safer Sign-Out Tool Kit

The most publicized ED tool is Safer Sign Out from the Emergency Medicine Patient Safety Foundation (EMPSF), a third-party nonprofit organization founded in 2003.12 Safer Sign Out focuses on using a physical checklist, dedicated time to sign-out, bidirectional communication, and confirmation of the sign-out with staff. The EMPSF provides all of the necessities to implement their sign-out tool department-wide, including training videos and pre- and postsurveys, in addition to the tool itself. The kit costs $1,695 to implement at a single site.¹² Although widely publicized, this toolkit has not yet been externally validated in the peer-reviewed literature.

Sign-Out Checklist

On a smaller scale, Dubosh et al¹³ recently found success using a sign-out checklist with residents in the ED at a single institution (See Box). The components of their checklist included history of present illness (HPI), ED course, pending studies, likely disposition, possible issues, and algorithms for disposition. In this study, trained research assistants monitored the sign-outs before and after implementation of the checklist. There were statistically significant improvements in the areas of HPI, ED course, possible diagnosis, and team awareness of the treatment plan. Of note, there was no difference in the amount of time required for sign-out with and without the checklist (1.42 vs 1.39 minutes, respectively).¹³ (See the Box for a convenient pocket-sized reproduction of the sign-out tool.)

ABC of Handover Tool

Developed in the United Kingdom, the ABC of Handover tool was specifically designed for use in the ED. This tool focuses on departmental awareness prior to specific patient sign-outs. The full-sheet paper checklist includes bed allocations in the ED and the hospital; available colleagues and consultants; a list of any deaths or dangerously ill patients; and equipment review. .¹⁴ The ABC of Handover tool is essentially a preamble to patient specifics compiled by surveying ED staff and attending physicians at a single urban center. It has not yet been validated in the peer-reviewed literature.¹⁴

ACEP Recommendations

Although ACEP does not endorse a particular sign-out tool,¹¹ its Section of Quality Improvement and Patient Safety created a framework of ED sign-outs and recommendations in which EPs should adhere to the following protocol:

• Limit unnecessary patient handoffs;
• Limit interruptions and distractions during sign-out;
• Provide a succinct overview; </lli>
• Highlight remaining tasks, plans, and possible changes for each patient;
• Have laboratory and imaging studies available during sign-out;
• Encourage bidirectional discourse about the assessments and treatment plans;
• Account for all patients; and
• Clearly signal the moment of full-care transfer.

I-PASS Handoff System

The I-PASS Handoff System is a landmark multicenter pediatric intervention largely funded by the US Department of Health and Human Services. The mnemonic I-PASS stands for the following:

• Illness severity;
• Patient summary;
• Action items;
• Situation awareness and contingency planning; and
• Synthesis by the receiver.

This system is part of a complete curriculum for pediatrics residents published in 2014.¹⁵ Single-center prospective validation found a 45.9% relative risk reduction in preventable medical errors without an increase in verbal sign-out length (32.3 minutes before the intervention vs 33.3 minutes after the intervention).⁶ This was confirmed in a multicenter prospective validation that found a 23% relative reduction in preventable medical errors—also without a change in sign-out length with versus without the tool (2.4 minutes vs 2.5 minutes, respectively).¹⁶ The bundle and curriculum are available for free and may be accessed online.¹⁵

SBAR Tool

The Situation, Background, Assessment, and Recommendation (SBAR) is the time-honored tool most well known in nursing—one that is of benefit to physicians as well.¹⁷ In one study, SBAR demonstrated a reduction in unexpected deaths hospital-wide at a single institution when nurses used it to communicate with physicians.¹⁸ Additional support, however, is largely based on nurse and physician perception of improved communication and more thorough handoffs.^19,20

Format and Outcomes

The format of a sign-out does not appear to influence outcomes, though acronyms and mnemonics appear effective—eg, I-PASS,¹⁶ SBAR,¹⁷ and IMOUTA²¹ (an otolaryngology resident tool that stands for identifying data, medical course, outcomes possible tonight, and responsibilities to do tonight). Riesenberg et al⁵ provide an overview of 24 different mnemonics described in the handoff literature.

In addition to mnemonic tools, paper pocket cards²² and electronic medical record prompts¹³ also appear effective. Regardless of which tool is employed, the common theme is practice standardization with dedicated time for open commun¬ication.

Practical Challenges

Aside from standardization, there are numerous other factors that can lead to a poor sign-out experience in the ED. These include a loud and disruptive background; the uncertainty of who the charge physician is post-sign-out when both are still physically present; lack of “red flags” that help identify dangerous hand-offs; the goal to be concise; and the economic structure of the physician group.^1,5 These systems issues each need to be addressed; however, a standardized hand-off can decrease the margin of error and is relatively easy to implement.

Conclusion

Sign-outs are central to patient care, especially in the ED. Achieving the most effective sign-outs possible is of paramount importance and is deeply supported by respected physician groups.^11,12,17,23 Several ED-specific standardized sign-outs exist with varying emphases and empirical support. The method with the most empirical support is the pediatrics initiative, I-PASS, and is one that should be considered by EPs and departments when selecting a standardized method. Even if a department is not adopting a particular method, individual clinicians can implement a standardized sign-out in their own daily practice—beginning with the next shift. A safe and effective sign-out in a reasonable timeframe in a busy ED is not only possible, but imperative.

Dr Phillips is a senior resident in the Stanford/Kaiser Emergency Medicine Residency, Stanford University School of Medicine, California. Mr Malamet is a fourth-year medical student at Philadelphia College of Osteopathic Medicine, Pennsylvania. Dr Williams is the associate program director for the Stanford/Kaiser Emergency Medicine Residency and a clinical associate professor, Surgery - Emergency Medicine at Stanford University School of Medicine, California.

Disclosure Statement: The authors express no conflicts of interest. The views expressed in this article are those of the author and do not represent the official position of the US Air Force, Department of Defense, or US Government.

Emergency medicine and critical care medicine share a responsibility for the care of acutely ill patients with life-threatening pathologies. The skills required of both emergency physicians (EPs) and critical care specialists to recognize, diagnose, and resuscitate such patients have resulted in many shared guidelines, recommendations, and publications. When critically ill patients enter the hospital through the ED, the care provided by EPs greatly impacts both the early and long-term outcomes. It is not uncommon for critically ill patients to spend several hours under the care of an EP while awaiting an available inpatient bed in the intensive care unit (ICU) or “step down” monitored unit. 

This article provides a summary review of current guidelines, evidence-based medicine recommendations, and the results of recent trials involving ventilator management, treatment of sepsis, management of hypertension accompanying neurological emergencies, and the selection of pressors for the treatment of different shock states. 

Ventilator Management

Mechanical ventilation is frequently undertaken in the ED for patients with respiratory failure—the origin of which is not always immediately clear. Data from the National Heart, Lung, and Blood Institute’s (NHLBI) acute respiratory distress syndrome (ARDS) clinical network (http://www.ardsnet.org) and other clinical trials have established the benefit of low tidal-volume, “lung-protective” ventilation in the patient with ARDS.^1,2 Numerous studies have also shown the benefit of low-tidal-volume (TV), ventilation in patients without ARDS, and its use is now the standard of care for a large range of respiratory conditions causing compromise.³

The prompt initiation of lung-protective ventilation has a significant impact on reducing ICU mortality.⁴ A recent retrospective review of 3.5 million ED visits showed the median length of stay for patients started on mechanical ventilation in the ED to be greater than 3 hours.⁵ Such a length of time on mechanical ventilation in this setting can have significant effects on the course of illness; however, it is not clear whether mechanical ventilation performed in the ED typically conforms to evidence-based standards. In one study performed in an academic center, less than one-third of patients with sepsis and respiratory failure received low-volume ventilation in the ED.⁶ Another study suggested that emergency medicine residents may not receive as much dedicated education on the initial management of ventilators as needed—despite the potentially unforgiving physiologic process of positive-pressure mechanical ventilation.⁷

The fundamental principles required to safely manage most patients in respiratory failure are not difficult to master. There are several simple evidence-based ventilator strategies for managing patients with respiratory failure. The three primary principles of initiating and providing effective mechanical ventilation are: (1) avoiding traumatic ventilation; (2) maintaining normoxia; and (3) maintaining appropriate acid-base balance. Each of these principles can be achieved in a stepwise fashion.

Step I: Establishing Lung-Protective Settings on the Ventilator

Three central parameters must be selected at the initiation of assist-control mechanical ventilation: TV, respiratory rate (RR), and positive end-expiratory pressure (PEEP). These parameters have been extensively studied, and there is excellent evidence to guide the EP in choosing the correct settings.

Tidal Volume. Although the normal human lung can accommodate about 6 L of air, in cases of respiratory failure, the surface area available for gas exchange is significantly reduced due to a pathologic process undermining entire regions of the air-blood interface. Consequently, a person whose normal lungs are suddenly required to perform the life-sustaining gas exchanges in critical illness with the much smaller lung surface is at a significant disadvantage.

The widely accepted lung-protective volumes range from 6 to 8 mL/kg of predicted body weight (PBW), a height-based calculation.⁸ For example, in a 6-foot tall man, 6 mL/kg of PBW amounts to a TV of 466 mL; in a 5-foot tall woman, the same amount of PBW amounts to a TV of 273 mL. Volumes may be referenced using PBW tables from the NHLBI ARDS network or by employing the following equations:

Adult men: PBW (kg) = 50 + 2.3 (height [in] – 60)

Adult women: PBW (kg) = 45.5 + 2.3 (height [in] – 60).⁹

Respiratory Rate. The RR should be set somewhat higher than normal because the TV per breath has been slightly reduced, and also because sick patients in a catabolic state may have larger minute ventilations than they would when healthy. As previously described, since the TV is restricted, RR is the most mobile parameter in maintaining appropriate minute ventilation. Minute ventilation (MV) is the product of RR multiplied by TV (MV = RR x TV), and this should be calculated to approximate the patient’s own efforts, which are dependent upon the clinical circumstances. For example, patients whose bodies are trying to compensate for an acidosis will require much higher rates than those who are simply obtunded and intubated for airway protection. In other words, in order to remove carbon dioxide (CO₂) in an acidemic patient, a higher RR rate may be required, whereas a lower rate may be selected to compensate for alkalemia while maintaining appropriate oxygen (O₂) levels in both cases.¹⁰

Positive End-Expiratory Pressure. Previous recommendations for ventilation in respiratory failure called for large TVs (ie, 10 to 15 mL/kg), partly out of concern that smaller volumes would promote distal airway collapse, thereby increasing the amount of lung that received blood but not air, consequently worsening overall oxygenation.¹¹ Although administering such large volumes has clearly proved harmful, the valid concern about distal airway collapse can be addressed in part by adjustments to PEEP, which acts to “stent” open airways after most of the tidal breath has left the airways.

Positive end-expiratory pressure, however, is not without risks.¹² Blood from the rest of the body will encounter resistance returning to a thoracic cavity persistently inflated by positive pressure, and this decrease in preload may contribute to hypotension. Similarly, a weak right ventricle may struggle to push blood into the compressed pulmonary vasculature, increasing the cardiac workload and further compromising hemodynamics.¹³ In general, PEEP should be set as low as the maintenance of adequate oxygenation permits. The NHLBI ARDS guidelines provide a table on balancing PEEP and the fraction of inspired O₂ (FiO₂), as well as hypotension, in refractory hypoxemic patients—with the limitation on PEEP set by the patients’ pulmonary compliance (plateau pressures, discussed next).⁸

After making these selections, several parameters must be monitored closely.  Those most relevant to lung-protective ventilation are the peak airway pressure and, most importantly, the plateau pressure. Numerous animal studies now demonstrate serious lung injury in both healthy and diseased lungs from high peak pressures (defined as a plateau pressure >30 cm water [H₂O]).^14,15 A high-pressure alarm sounding on the ventilator must be promptly addressed by an evaluation for easily reversible causes, such as tube obstruction, pneumothorax, breath stacking, pulmonary edema, or pleural effusions. A full discussion of the causes of elevated peak and plateau pressures is beyond the scope of this review, but if the plateau pressures remain consistently high, a reduction in TV may be necessary.

Step II: Maintaining Normoxia

As a severely hypoxic patient will rapidly decompensate with progression to death, a host of monitoring devices are used to alert the nurse or physician that O₂ levels have fallen below the normal range. Strategies to manage refractory hypoxia in the ventilated patient are complex. For most patients, 100% FiO₂ is initiated immediately after intubation to increase the safety of the procedure, but there is animal evidence that high O₂ levels promote inflammatory responses, and human data suggest hyperoxia can be deleterious to long-term outcomes, particularly following cardiac arrest and stroke.^16,17 A persistent O₂ saturation of 100% on pulse oximetry or a supraphysiologic partial pressure of O₂ (PaO₂) on an arterial blood gas (defined as >200 mm Hg) may actually cause the patient more harm than good. Therefore, the fraction of inspired O₂ should be titrated to maintain normoxia. The ARDS protocol, for example, targets an O₂ saturation of 88% to 95% and a PaO₂ of 55 to 80 mm Hg.⁸

Step III: Maintaining Acid-Base Balance

The basic principles of acid-base physiology should be familiar to EPs. When a patient is sedated and the airway secured, the primary means by which blood pH is maintained is now in the hands of the intubating physician. Patients with respiratory failure may have compensated for a preexisting derangement in their blood pH. If the preexisting condition is not recognized and ventilator settings are not maintained appropriately, they may be vulnerable to developing another derangement. Even on settings that allow the patient to breathe over a set rate, the sedation required to tolerate an endotracheal tube may cause significant respiratory depression, making it impossible for the patient to auto-regulate the respiratory component of acid-base homeostasis (ie, by hyperventilation). 

As in the discussion of RR, TVs are “fixed” based on low-TV lung-protective ventilation. Therefore, changing the patient’s set RR is the easiest method to adjust the partial pressure of CO₂ (PaCO₂), and consequently address any respiratory acidosis. An increase in the RR will increase the patient’s minute ventilation, leading to a decrease in serum PaCO₂ levels, whereas a decrease in the RR will have the converse effect. It is important to obtain an arterial blood-gas reading shortly after intubation and to continue to monitor the impact of any ventilator titrations on the patient’s acid-base status.

Studies of “permissive hypercapnia” in ARDS patients have shown that prioritizing lung-protective ventilator settings, even at the expense of a normal CO₂, reduce mortality.^1,18 Even in situations where it is not necessary to maintain hypercapnia for lung-protective settings, the hypercapnia appears to have beneficial effects.^19-21 No upper limits on hypercapnia have been established, and even extreme levels have been associated with successful patient outcomes.²² However, a study by Hickling et al²³ demonstrated that an initial trial of lung-protective ventilation demonstrated benefit from unbuffered hypercarbia and acidosis, reporting an average CO₂ level of 66 and a pH of 7. These guidelines should be appropriate for use in the ED.

In summary, assuming control of a patient’s respiratory system—with its nuanced and responsive role in acid-base, oxygenation, and cardiopulmonary hemodynamics—is one of the most difficult situations routinely encountered by an EP. While the procedure itself may be life-saving, the next several hours can have significant impact on the patient’s long-term outcome.

Treating Sepsis and Surviving Sepsis: Recommendations Versus the ARISE/ProCESS Trials

Sepsis and Septic Shock

Sepsis is defined as an infection plus systemic inflammatory response syndrome (SIRS). Severe sepsis is sepsis plus sepsis-induced organ dysfunction or tissue hypoperfusion resulting in or caused by lactic acidosis, acute lung injury, altered mental status, or coagulation abnormalities. Septic shock refers to persistent sepsis-induced hypotension despite adequate fluid resuscitation.²⁴ The ambiguity of these definitions may invariably lead to a practitioner’s underappreciation or misconception of the importance of sepsis.

Sepsis is one of the most common, yet least-recognized, entities. In the United States, it is estimated that 3 in 1,000 people annually are affected by sepsis, and every few seconds, a person dies of sepsis.²⁵ Both numbers underestimate the effects on the elderly. Clinical manifestations of sepsis vary, and the condition may originate from both community-acquired and healthcare-associated sources.

In 2001, a landmark study demonstrated that early goal-directed therapy (EGDT) reduced mortality and improved patient outcomes in patients presenting to the ED in severe sepsis.²⁶ The estimated 12% to 16% reduction in mortality reported in this trial began an initiative to broaden the scope and awareness of sepsis.

Current Literature and Evidence-Based Guidelines

The most recent guidelines for the management of septic shock from the Surviving Sepsis Campaign are summarized in Table 1. With its last revision, the Surviving Sepsis guidelines of 2012 has two main management foci—initiating treatment within the first 3 and the first 6 hours after recognition within the first 3 hours and those within the first 6 hours after sepsis recognition (Table 2). Within the first 3 hours, the treatment team should draw a serum lactate level; obtain cultures prior to the administration of antibiotics; initiate broad-spectrum antibiotics as early as possible; and administer 20 to 30 mL/kg of crystalloid fluids in patients with hypotension or a lactate level greater than 4 mmol/L. Within the first 6 hours, the clinician should administer intravenous (IV) vasopressors, preferentially norepinephrine, for persistent hypotension after a fluid challenge to maintain a mean arterial pressure >65 mm Hg; place a supra-diaphragmatic central venous catheter to measure a serum mixed venous O₂ saturation (ScvO₂) and central venous pressure (CVP); and measure serial serum lactate levels if they were initially elevated (lactate ≥4 mmol/L [36 mg/dL]).^24,30,31 The targets for ScvO₂ and CVP are ≥70%, and >8 mm Hg, respectively.

Summary

Sepsis is a prevalent ED presentation associated with mortality that can present in a complex fashion. Early recognition and management is essential and can be condensed into a few key recommendations. Becoming familiar with and incorporating these recommendations into daily practice will enable EPs to deliver quality care to every patient presenting with sepsis, and will also reduce mortality.

Blood Pressure Management for Select Neurological Emergencies

Patients with ischemic stroke, spontaneous intracerebral hemorrhage (ICH), and aneurysmal subarachnoid hemorrhage (SAH) often present with elevated blood pressures (BPs).^34-36 In caring for these patients, EPs face the question of how, or even if, the patient’s BP should be managed. What are the appropriate BP targets for each of the aforementioned pathologies? Does aggressive BP management benefit or harm the patient?

Background

The relationship between hypertension and stroke is different for each stroke type. Retrospective data show a U-shaped relationship between BP and mortality in ischemic stroke, with the highest mortality observed at both extremes of the BP curve.³⁴ Data also suggest increased mortality when ICH is accompanied by hypertension.³⁵ Hypertension may also be associated with a higher risk of rebleeding in patients with SAH due to aneurysms.³⁶ Because of the variable relationship between stroke and hypertension, therapeutic recommendations for each type of stroke can be confusing.

Current Literature and Evidence-Based Guidelines

Firm evidence to make therapeutic recommendations remains elusive. The recent American Heart Association (AHA) guidelines covering ischemic stroke, ICH, and SAH were published between late 2010 and early 2013, and several trials investigating the role of BP control in ischemic and hemorrhagic stroke have subsequently been published.^37-41

When the Cochrane Collaboration updated its systematic review on vasoactive medications in stroke in 2014 to include recent evidence,⁴² it ultimately concluded that lowering BP does not improve mortality, neurological deterioration, or quality of life regardless of stroke type, and suggest that further investigations should be undertaken.⁹ However, the Cochrane authors noted that two recent trials showed a statistically significant association between improved quality of life and BP reduction within 6 hours of stroke onset.^38-39 Although the data were compiled from just 2,835 patients of the 15,432 included in the entire Cochrane review, it suggested that interventions initiated in the ED may contribute to any potential beneficial outcomes from intensive BP control.

Ischemic Stroke

The China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) investigated the initiation of BP-control measures within 48 hours of onset of ischemic stroke in approximately 4,000 patients and found no significant difference in death or disability between the group that received BP-control interventions and the group that did not.³⁷ The Rapid Intervention With Glyceryl Trinitrate in Hypertensive Stroke Trial (RIGHT) included patients with both ischemic and hemorrhagic strokes. Though it studied only 41 patients, this trial suggests that early BP control is safe and may be associated with lower disability.³⁸ These findings are bolstered by the more recent Efficacy of Nitric Oxide in Stroke (ENOS) trial showing a similar safety profile for BP control in both ischemic and hemorrhagic strokes, though the mean difference in systolic BP after therapy was a mere 7 mm Hg.⁴⁰ The combined data from the RIGHT and ENOS trials offer little to clarify the question of appropriate BP control.

For now, the EP is left with the AHA/American Stroke Association (ASA) guideline’s recommendation “not to lower the BP during the initial 24 hours of acute ischemic stroke unless the BP is greater than 220/120 mm Hg.”³⁴ The recommendation differs in cases when a patient receives thrombolytics and hemorrhagic transformation is a risk. There have been no new data to change the AHA/ASA’s recommendations for patients receiving thrombolytics. In such cases, the EP should ensure the patient’s BP is below 185/110 mm Hg prior to thrombolytic administration and below 180/105 mm Hg during therapy.³⁴ A variety of agents is available to lower BP in this situation, and includes IV labetalol, nicardipine, esmolol, and others.

Intracerebral Hemorrhage

The recent literature on blood pressure control in ICH has also increased since the most recent AHA/ASA recommendations. The Second Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT-2 included over 2,800 patients randomized to intensive early therapy to reduce BP to less than 140 mm Hg or less than 180 mm Hg and found no significant difference in mortality or safety between the two groups, though intensive therapy was associated with less disability.³⁹ The Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial (ICH-ADAPT) trial further clarified the issue of safety during intensive BP control by showing no decrease in perihematomal cerebral blood flow in patients whose BP control was targeted to less than 150 mm Hg compared to those whose BP was less than 180 mm Hg, suggesting that aggressive BP reduction does not cause iatrogenic ischemic stroke.⁴¹

These combined data suggest that intensive BP management is safe for patients with ICH, providing reassurance for the AHA/ASA guideline recommendation that “in patients…with a systolic BP of 150 to 220 mm Hg, acute lowering of systolic BP to 140 mm Hg is probably safe.”³⁵ Whether this improves patient outcomes remains unclear. Again, multiple agents are available for BP control, including IV labetalol or nicardipine, with no agent identified as superior in producing better patient outcomes. A continuous infusion is recommended if several boluses are ineffective in achieving and maintaining the target BP, as BP variability has been associated with poorer outcomes.⁴³

Subarachnoid Hemorrhage

There are no large recent studies in the literature on antihypertensive therapy in SAH. The AHA/ASA guidelines updated in 2012 reflect the consensus that elevated BPs are associated with increased risk of aneurysmal rebleeding and thus poorer patient-oriented outcomes. The consensus remains to use a titratable agent to target a systolic BP less than 160 mm Hg until definitive neurosurgical therapy, such as aneurysmal coiling or clipping.³⁶ Given the variability of the sodium nitroprusside dose-response relationship, IV labetalol, and nicardipine, are  recommended agents for continuous control, though data showing differences in mortality and/or disability are lacking.³⁶ Again, retrospective data suggest that BP variability negatively impacts mortality and disability, so consider early initiation of continuous infusions to achieve and maintain consistency in the chosen target.⁴⁴

Summary

Pressors in the Management of Hypotension

Norepinephrine

Norepinephrine is one of the most commonly used agents for shock in the ED, with indications spanning multiple etiologies. It is an endogenous neurotransmitter that works predominantly on a₁ receptors as well as exerting some modest effects on b₁ and b₂ receptors, for combined vasopressor and improved cardiac contractility effect.^46-47 Norepinephrine is currently the recommended initial agent for sepsis-induced tissue hypoperfusion.²⁴ However, a recent Cochrane systematic review and meta-analysis supports evidence of limited differences among various pressors.⁴⁸ Several comparative randomized control trials show norepinephrine is as effective as other agents, but with fewer side effects.^24,49 With the ease and familiarity of its use by most EPs, and a wide therapeutic index for targeted effect versus arrhythmias, norepinephrine is a reasonable choice as the initial pressor in managing a wide variety of shock syndromes.

Vasopressin

Another commonly used agent in the treatment of shock, vasopressin is an analogue of the antidiuretic hormone secreted from the posterior pituitary gland, exerting its CV effects primarily as a vasoconstrictor by increasing intracellular calcium.⁵⁰ Vasopressin doses are 0.03 or 0.04 U/min IV without titration.^24,50 Early studies of septic patients demonstrated a relative deficiency of serum vasopressin levels, leading clinicians to utilize it in the treatment of sepsis-induced shock. However, the Vasopressin and Septic Shock Trial (VASST) trial demonstrated that the addition of vasopressin to norepinephrine did not produce any improvements in morbidity or mortality compared with norepinephrine alone.⁵¹ Despite these findings, vasopressin is still commonly used as a secondary agent to correct continued hypotension. Vasopressin may be appropriate for patients who specifically require peripheral vasoconstriction in the setting of good cardiac output and volume status, ability to tolerate increases in afterload, or in patients at risk for dysrhythmias.

Dopamine

Dopamine had been previously recommended as the initial choice of pharmacologic support for the management of shock.^24,52-54 Dopamine is an adrenergic agonist agent that works via a₁ and b₁ receptors as well as a precursor to the synthesis of norepinephrine and epinephrine.⁵⁵ There are dose-dependent effects on various receptors from escalating amounts administered,^55-56  but the literature does not support the concept of “renal-dose” dopamine.^57-59 A study by DeBaker et al⁴⁹ suggested no difference in efficacy between dopamine and norepinephrine, but demonstrated a greater tendency toward cardiac dysrhythmias with dopamine. For these reasons noted above, norepinephrine may be the initial agent for pharmaceutical support of shock, particularly in septic syndromes, with dopamine as a secondary or adjunct agent in patients at low risk for tachyarrhythmia or a relative bradycardia. ^{24, 56}

Dobutamine

Dobutamine is another adrenergic agonist that is similar to dopamine but with a greater effect on inotropic cardiac contractility due to a preferential action at b₁ receptors.⁶⁰ It can potentially induce peripheral vasodilatation due to its effect on arterial b₁ receptors.  Given this balance, dobutamine is an agent that should be utilized for cardiogenic shock when increased contractility is needed. These effects are particularly useful in patients with “wet and cold” heart failure who have a low cardiac output and volume-overloaded status.^{61, 62} However, it may be necessary to add another agent to provide additional peripheral vasoconstriction should the use of dobutamine affect lead to excessive vasodilatation.  

Epinephrine

One of the most powerful vasoactive agents, epinephrine has a high affinity for all b₁, b₂ and a₁ receptors.⁶³ These combined effects lead to increased cardiac output and improved BP by increasing cardiac contractility and peripheral vasoconstriction. The effect of epinephrine in limiting mast cell release of histamine makes it the preferred choice for the treatment of anaphylaxis.⁶⁴ However, side effects of epinephrine include hypertension, tachydysrhythmias, tissue ischemia from vigorous vasoconstriction, and induced lactic acidosis.⁶³

Phenylephrine

Phenylephrine is an a-adrenergic agonist that activates a₁ receptors on arteriole smooth muscle, resulting in vasoconstriction.⁶⁵ It is currently recommended only for hypotension related to procedural sedation.⁴⁷ Phenylephrine is not recommended for treating patients with septic shock, except when there are concerns about tachydysrhythmias; persistent hypotension with a high cardiac output after treatment with other vasoconstrictor and inotropic drugs; or when a “pure” vasoconstrictor may be preferred.^24,56,65

Summary

Although there are many other vasoactive agents that can be used, the selected agents discussed above represent those most commonly used in the ED. All demonstrate significant crossover effects and receptor activation, as well as impact on cardiac contractility and vasoconstriction. The suggested specific indications for each agent are based on current evidenced-based medicine, clinical guidelines, and theoretical benefits on clinical scenarios. But, as always, clinical decisions should be individualized for critically ill patients.

Conclusion

The resuscitation and initiation of care for critically ill patients must typically be immediately upon their arrival in the ED. While general guidelines or recommendations exist for commonly encountered pathologies, treatment should always be patient-centered, based on the needs and nuances unique to each patient in this vulnerable population. The initiation of mechanical ventilation, treatment of sepsis, management of hypertensive neurosurgical emergencies, and use of pressors in shock states are among the most critically important tasks an EP is called upon to perform. This review of current evidence-based guidelines and recommendations will help EPs provide the appropriate and unique care each patient requires.

Dr Brubaker is a resident in the department of emergency medicine at the University of Pittsburgh, Pennsylvania. Dr Yu is a fellow of adult critical care medicine – emergency medicine in the department of critical care medicine, University of Pittsburgh Medical Center, Pennsylvania. Dr Goodmanson is a resident in the department of emergency medicine at the University of Pittsburgh, Pennsylvania. Dr Schott is an assistant professor, department of emergency medicine and critical care medicine; assistant director of ultrasonography; director, critical care elective student rotation; and director, point of care ultrasound elective student rotation, at the University of Pittsburgh, Pennsylvania

Emergency medicine and critical care medicine share a responsibility for the care of acutely ill patients with life-threatening pathologies. The skills required of both emergency physicians (EPs) and critical care specialists to recognize, diagnose, and resuscitate such patients have resulted in many shared guidelines, recommendations, and publications. When critically ill patients enter the hospital through the ED, the care provided by EPs greatly impacts both the early and long-term outcomes. It is not uncommon for critically ill patients to spend several hours under the care of an EP while awaiting an available inpatient bed in the intensive care unit (ICU) or “step down” monitored unit. 

This article provides a summary review of current guidelines, evidence-based medicine recommendations, and the results of recent trials involving ventilator management, treatment of sepsis, management of hypertension accompanying neurological emergencies, and the selection of pressors for the treatment of different shock states. 

Ventilator Management

Mechanical ventilation is frequently undertaken in the ED for patients with respiratory failure—the origin of which is not always immediately clear. Data from the National Heart, Lung, and Blood Institute’s (NHLBI) acute respiratory distress syndrome (ARDS) clinical network (http://www.ardsnet.org) and other clinical trials have established the benefit of low tidal-volume, “lung-protective” ventilation in the patient with ARDS.^1,2 Numerous studies have also shown the benefit of low-tidal-volume (TV), ventilation in patients without ARDS, and its use is now the standard of care for a large range of respiratory conditions causing compromise.³

The prompt initiation of lung-protective ventilation has a significant impact on reducing ICU mortality.⁴ A recent retrospective review of 3.5 million ED visits showed the median length of stay for patients started on mechanical ventilation in the ED to be greater than 3 hours.⁵ Such a length of time on mechanical ventilation in this setting can have significant effects on the course of illness; however, it is not clear whether mechanical ventilation performed in the ED typically conforms to evidence-based standards. In one study performed in an academic center, less than one-third of patients with sepsis and respiratory failure received low-volume ventilation in the ED.⁶ Another study suggested that emergency medicine residents may not receive as much dedicated education on the initial management of ventilators as needed—despite the potentially unforgiving physiologic process of positive-pressure mechanical ventilation.⁷

The fundamental principles required to safely manage most patients in respiratory failure are not difficult to master. There are several simple evidence-based ventilator strategies for managing patients with respiratory failure. The three primary principles of initiating and providing effective mechanical ventilation are: (1) avoiding traumatic ventilation; (2) maintaining normoxia; and (3) maintaining appropriate acid-base balance. Each of these principles can be achieved in a stepwise fashion.

Step I: Establishing Lung-Protective Settings on the Ventilator

Three central parameters must be selected at the initiation of assist-control mechanical ventilation: TV, respiratory rate (RR), and positive end-expiratory pressure (PEEP). These parameters have been extensively studied, and there is excellent evidence to guide the EP in choosing the correct settings.

Tidal Volume. Although the normal human lung can accommodate about 6 L of air, in cases of respiratory failure, the surface area available for gas exchange is significantly reduced due to a pathologic process undermining entire regions of the air-blood interface. Consequently, a person whose normal lungs are suddenly required to perform the life-sustaining gas exchanges in critical illness with the much smaller lung surface is at a significant disadvantage.

The widely accepted lung-protective volumes range from 6 to 8 mL/kg of predicted body weight (PBW), a height-based calculation.⁸ For example, in a 6-foot tall man, 6 mL/kg of PBW amounts to a TV of 466 mL; in a 5-foot tall woman, the same amount of PBW amounts to a TV of 273 mL. Volumes may be referenced using PBW tables from the NHLBI ARDS network or by employing the following equations:

Adult men: PBW (kg) = 50 + 2.3 (height [in] – 60)

Adult women: PBW (kg) = 45.5 + 2.3 (height [in] – 60).⁹

Respiratory Rate. The RR should be set somewhat higher than normal because the TV per breath has been slightly reduced, and also because sick patients in a catabolic state may have larger minute ventilations than they would when healthy. As previously described, since the TV is restricted, RR is the most mobile parameter in maintaining appropriate minute ventilation. Minute ventilation (MV) is the product of RR multiplied by TV (MV = RR x TV), and this should be calculated to approximate the patient’s own efforts, which are dependent upon the clinical circumstances. For example, patients whose bodies are trying to compensate for an acidosis will require much higher rates than those who are simply obtunded and intubated for airway protection. In other words, in order to remove carbon dioxide (CO₂) in an acidemic patient, a higher RR rate may be required, whereas a lower rate may be selected to compensate for alkalemia while maintaining appropriate oxygen (O₂) levels in both cases.¹⁰

Positive End-Expiratory Pressure. Previous recommendations for ventilation in respiratory failure called for large TVs (ie, 10 to 15 mL/kg), partly out of concern that smaller volumes would promote distal airway collapse, thereby increasing the amount of lung that received blood but not air, consequently worsening overall oxygenation.¹¹ Although administering such large volumes has clearly proved harmful, the valid concern about distal airway collapse can be addressed in part by adjustments to PEEP, which acts to “stent” open airways after most of the tidal breath has left the airways.

Positive end-expiratory pressure, however, is not without risks.¹² Blood from the rest of the body will encounter resistance returning to a thoracic cavity persistently inflated by positive pressure, and this decrease in preload may contribute to hypotension. Similarly, a weak right ventricle may struggle to push blood into the compressed pulmonary vasculature, increasing the cardiac workload and further compromising hemodynamics.¹³ In general, PEEP should be set as low as the maintenance of adequate oxygenation permits. The NHLBI ARDS guidelines provide a table on balancing PEEP and the fraction of inspired O₂ (FiO₂), as well as hypotension, in refractory hypoxemic patients—with the limitation on PEEP set by the patients’ pulmonary compliance (plateau pressures, discussed next).⁸

After making these selections, several parameters must be monitored closely.  Those most relevant to lung-protective ventilation are the peak airway pressure and, most importantly, the plateau pressure. Numerous animal studies now demonstrate serious lung injury in both healthy and diseased lungs from high peak pressures (defined as a plateau pressure >30 cm water [H₂O]).^14,15 A high-pressure alarm sounding on the ventilator must be promptly addressed by an evaluation for easily reversible causes, such as tube obstruction, pneumothorax, breath stacking, pulmonary edema, or pleural effusions. A full discussion of the causes of elevated peak and plateau pressures is beyond the scope of this review, but if the plateau pressures remain consistently high, a reduction in TV may be necessary.

Step II: Maintaining Normoxia

As a severely hypoxic patient will rapidly decompensate with progression to death, a host of monitoring devices are used to alert the nurse or physician that O₂ levels have fallen below the normal range. Strategies to manage refractory hypoxia in the ventilated patient are complex. For most patients, 100% FiO₂ is initiated immediately after intubation to increase the safety of the procedure, but there is animal evidence that high O₂ levels promote inflammatory responses, and human data suggest hyperoxia can be deleterious to long-term outcomes, particularly following cardiac arrest and stroke.^16,17 A persistent O₂ saturation of 100% on pulse oximetry or a supraphysiologic partial pressure of O₂ (PaO₂) on an arterial blood gas (defined as >200 mm Hg) may actually cause the patient more harm than good. Therefore, the fraction of inspired O₂ should be titrated to maintain normoxia. The ARDS protocol, for example, targets an O₂ saturation of 88% to 95% and a PaO₂ of 55 to 80 mm Hg.⁸

Step III: Maintaining Acid-Base Balance

The basic principles of acid-base physiology should be familiar to EPs. When a patient is sedated and the airway secured, the primary means by which blood pH is maintained is now in the hands of the intubating physician. Patients with respiratory failure may have compensated for a preexisting derangement in their blood pH. If the preexisting condition is not recognized and ventilator settings are not maintained appropriately, they may be vulnerable to developing another derangement. Even on settings that allow the patient to breathe over a set rate, the sedation required to tolerate an endotracheal tube may cause significant respiratory depression, making it impossible for the patient to auto-regulate the respiratory component of acid-base homeostasis (ie, by hyperventilation). 

As in the discussion of RR, TVs are “fixed” based on low-TV lung-protective ventilation. Therefore, changing the patient’s set RR is the easiest method to adjust the partial pressure of CO₂ (PaCO₂), and consequently address any respiratory acidosis. An increase in the RR will increase the patient’s minute ventilation, leading to a decrease in serum PaCO₂ levels, whereas a decrease in the RR will have the converse effect. It is important to obtain an arterial blood-gas reading shortly after intubation and to continue to monitor the impact of any ventilator titrations on the patient’s acid-base status.

Studies of “permissive hypercapnia” in ARDS patients have shown that prioritizing lung-protective ventilator settings, even at the expense of a normal CO₂, reduce mortality.^1,18 Even in situations where it is not necessary to maintain hypercapnia for lung-protective settings, the hypercapnia appears to have beneficial effects.^19-21 No upper limits on hypercapnia have been established, and even extreme levels have been associated with successful patient outcomes.²² However, a study by Hickling et al²³ demonstrated that an initial trial of lung-protective ventilation demonstrated benefit from unbuffered hypercarbia and acidosis, reporting an average CO₂ level of 66 and a pH of 7. These guidelines should be appropriate for use in the ED.

In summary, assuming control of a patient’s respiratory system—with its nuanced and responsive role in acid-base, oxygenation, and cardiopulmonary hemodynamics—is one of the most difficult situations routinely encountered by an EP. While the procedure itself may be life-saving, the next several hours can have significant impact on the patient’s long-term outcome.

Treating Sepsis and Surviving Sepsis: Recommendations Versus the ARISE/ProCESS Trials

Sepsis and Septic Shock

Sepsis is defined as an infection plus systemic inflammatory response syndrome (SIRS). Severe sepsis is sepsis plus sepsis-induced organ dysfunction or tissue hypoperfusion resulting in or caused by lactic acidosis, acute lung injury, altered mental status, or coagulation abnormalities. Septic shock refers to persistent sepsis-induced hypotension despite adequate fluid resuscitation.²⁴ The ambiguity of these definitions may invariably lead to a practitioner’s underappreciation or misconception of the importance of sepsis.

Sepsis is one of the most common, yet least-recognized, entities. In the United States, it is estimated that 3 in 1,000 people annually are affected by sepsis, and every few seconds, a person dies of sepsis.²⁵ Both numbers underestimate the effects on the elderly. Clinical manifestations of sepsis vary, and the condition may originate from both community-acquired and healthcare-associated sources.

In 2001, a landmark study demonstrated that early goal-directed therapy (EGDT) reduced mortality and improved patient outcomes in patients presenting to the ED in severe sepsis.²⁶ The estimated 12% to 16% reduction in mortality reported in this trial began an initiative to broaden the scope and awareness of sepsis.

Current Literature and Evidence-Based Guidelines

The most recent guidelines for the management of septic shock from the Surviving Sepsis Campaign are summarized in Table 1. With its last revision, the Surviving Sepsis guidelines of 2012 has two main management foci—initiating treatment within the first 3 and the first 6 hours after recognition within the first 3 hours and those within the first 6 hours after sepsis recognition (Table 2). Within the first 3 hours, the treatment team should draw a serum lactate level; obtain cultures prior to the administration of antibiotics; initiate broad-spectrum antibiotics as early as possible; and administer 20 to 30 mL/kg of crystalloid fluids in patients with hypotension or a lactate level greater than 4 mmol/L. Within the first 6 hours, the clinician should administer intravenous (IV) vasopressors, preferentially norepinephrine, for persistent hypotension after a fluid challenge to maintain a mean arterial pressure >65 mm Hg; place a supra-diaphragmatic central venous catheter to measure a serum mixed venous O₂ saturation (ScvO₂) and central venous pressure (CVP); and measure serial serum lactate levels if they were initially elevated (lactate ≥4 mmol/L [36 mg/dL]).^24,30,31 The targets for ScvO₂ and CVP are ≥70%, and >8 mm Hg, respectively.

Summary

Sepsis is a prevalent ED presentation associated with mortality that can present in a complex fashion. Early recognition and management is essential and can be condensed into a few key recommendations. Becoming familiar with and incorporating these recommendations into daily practice will enable EPs to deliver quality care to every patient presenting with sepsis, and will also reduce mortality.

Blood Pressure Management for Select Neurological Emergencies

Patients with ischemic stroke, spontaneous intracerebral hemorrhage (ICH), and aneurysmal subarachnoid hemorrhage (SAH) often present with elevated blood pressures (BPs).^34-36 In caring for these patients, EPs face the question of how, or even if, the patient’s BP should be managed. What are the appropriate BP targets for each of the aforementioned pathologies? Does aggressive BP management benefit or harm the patient?

Background

The relationship between hypertension and stroke is different for each stroke type. Retrospective data show a U-shaped relationship between BP and mortality in ischemic stroke, with the highest mortality observed at both extremes of the BP curve.³⁴ Data also suggest increased mortality when ICH is accompanied by hypertension.³⁵ Hypertension may also be associated with a higher risk of rebleeding in patients with SAH due to aneurysms.³⁶ Because of the variable relationship between stroke and hypertension, therapeutic recommendations for each type of stroke can be confusing.

Current Literature and Evidence-Based Guidelines

Firm evidence to make therapeutic recommendations remains elusive. The recent American Heart Association (AHA) guidelines covering ischemic stroke, ICH, and SAH were published between late 2010 and early 2013, and several trials investigating the role of BP control in ischemic and hemorrhagic stroke have subsequently been published.^37-41

When the Cochrane Collaboration updated its systematic review on vasoactive medications in stroke in 2014 to include recent evidence,⁴² it ultimately concluded that lowering BP does not improve mortality, neurological deterioration, or quality of life regardless of stroke type, and suggest that further investigations should be undertaken.⁹ However, the Cochrane authors noted that two recent trials showed a statistically significant association between improved quality of life and BP reduction within 6 hours of stroke onset.^38-39 Although the data were compiled from just 2,835 patients of the 15,432 included in the entire Cochrane review, it suggested that interventions initiated in the ED may contribute to any potential beneficial outcomes from intensive BP control.

Ischemic Stroke

The China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) investigated the initiation of BP-control measures within 48 hours of onset of ischemic stroke in approximately 4,000 patients and found no significant difference in death or disability between the group that received BP-control interventions and the group that did not.³⁷ The Rapid Intervention With Glyceryl Trinitrate in Hypertensive Stroke Trial (RIGHT) included patients with both ischemic and hemorrhagic strokes. Though it studied only 41 patients, this trial suggests that early BP control is safe and may be associated with lower disability.³⁸ These findings are bolstered by the more recent Efficacy of Nitric Oxide in Stroke (ENOS) trial showing a similar safety profile for BP control in both ischemic and hemorrhagic strokes, though the mean difference in systolic BP after therapy was a mere 7 mm Hg.⁴⁰ The combined data from the RIGHT and ENOS trials offer little to clarify the question of appropriate BP control.

For now, the EP is left with the AHA/American Stroke Association (ASA) guideline’s recommendation “not to lower the BP during the initial 24 hours of acute ischemic stroke unless the BP is greater than 220/120 mm Hg.”³⁴ The recommendation differs in cases when a patient receives thrombolytics and hemorrhagic transformation is a risk. There have been no new data to change the AHA/ASA’s recommendations for patients receiving thrombolytics. In such cases, the EP should ensure the patient’s BP is below 185/110 mm Hg prior to thrombolytic administration and below 180/105 mm Hg during therapy.³⁴ A variety of agents is available to lower BP in this situation, and includes IV labetalol, nicardipine, esmolol, and others.

Intracerebral Hemorrhage

The recent literature on blood pressure control in ICH has also increased since the most recent AHA/ASA recommendations. The Second Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT-2 included over 2,800 patients randomized to intensive early therapy to reduce BP to less than 140 mm Hg or less than 180 mm Hg and found no significant difference in mortality or safety between the two groups, though intensive therapy was associated with less disability.³⁹ The Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial (ICH-ADAPT) trial further clarified the issue of safety during intensive BP control by showing no decrease in perihematomal cerebral blood flow in patients whose BP control was targeted to less than 150 mm Hg compared to those whose BP was less than 180 mm Hg, suggesting that aggressive BP reduction does not cause iatrogenic ischemic stroke.⁴¹

These combined data suggest that intensive BP management is safe for patients with ICH, providing reassurance for the AHA/ASA guideline recommendation that “in patients…with a systolic BP of 150 to 220 mm Hg, acute lowering of systolic BP to 140 mm Hg is probably safe.”³⁵ Whether this improves patient outcomes remains unclear. Again, multiple agents are available for BP control, including IV labetalol or nicardipine, with no agent identified as superior in producing better patient outcomes. A continuous infusion is recommended if several boluses are ineffective in achieving and maintaining the target BP, as BP variability has been associated with poorer outcomes.⁴³

Subarachnoid Hemorrhage

There are no large recent studies in the literature on antihypertensive therapy in SAH. The AHA/ASA guidelines updated in 2012 reflect the consensus that elevated BPs are associated with increased risk of aneurysmal rebleeding and thus poorer patient-oriented outcomes. The consensus remains to use a titratable agent to target a systolic BP less than 160 mm Hg until definitive neurosurgical therapy, such as aneurysmal coiling or clipping.³⁶ Given the variability of the sodium nitroprusside dose-response relationship, IV labetalol, and nicardipine, are  recommended agents for continuous control, though data showing differences in mortality and/or disability are lacking.³⁶ Again, retrospective data suggest that BP variability negatively impacts mortality and disability, so consider early initiation of continuous infusions to achieve and maintain consistency in the chosen target.⁴⁴

Summary

Pressors in the Management of Hypotension

Norepinephrine

Norepinephrine is one of the most commonly used agents for shock in the ED, with indications spanning multiple etiologies. It is an endogenous neurotransmitter that works predominantly on a₁ receptors as well as exerting some modest effects on b₁ and b₂ receptors, for combined vasopressor and improved cardiac contractility effect.^46-47 Norepinephrine is currently the recommended initial agent for sepsis-induced tissue hypoperfusion.²⁴ However, a recent Cochrane systematic review and meta-analysis supports evidence of limited differences among various pressors.⁴⁸ Several comparative randomized control trials show norepinephrine is as effective as other agents, but with fewer side effects.^24,49 With the ease and familiarity of its use by most EPs, and a wide therapeutic index for targeted effect versus arrhythmias, norepinephrine is a reasonable choice as the initial pressor in managing a wide variety of shock syndromes.

Vasopressin

Another commonly used agent in the treatment of shock, vasopressin is an analogue of the antidiuretic hormone secreted from the posterior pituitary gland, exerting its CV effects primarily as a vasoconstrictor by increasing intracellular calcium.⁵⁰ Vasopressin doses are 0.03 or 0.04 U/min IV without titration.^24,50 Early studies of septic patients demonstrated a relative deficiency of serum vasopressin levels, leading clinicians to utilize it in the treatment of sepsis-induced shock. However, the Vasopressin and Septic Shock Trial (VASST) trial demonstrated that the addition of vasopressin to norepinephrine did not produce any improvements in morbidity or mortality compared with norepinephrine alone.⁵¹ Despite these findings, vasopressin is still commonly used as a secondary agent to correct continued hypotension. Vasopressin may be appropriate for patients who specifically require peripheral vasoconstriction in the setting of good cardiac output and volume status, ability to tolerate increases in afterload, or in patients at risk for dysrhythmias.

Dopamine

Dopamine had been previously recommended as the initial choice of pharmacologic support for the management of shock.^24,52-54 Dopamine is an adrenergic agonist agent that works via a₁ and b₁ receptors as well as a precursor to the synthesis of norepinephrine and epinephrine.⁵⁵ There are dose-dependent effects on various receptors from escalating amounts administered,^55-56  but the literature does not support the concept of “renal-dose” dopamine.^57-59 A study by DeBaker et al⁴⁹ suggested no difference in efficacy between dopamine and norepinephrine, but demonstrated a greater tendency toward cardiac dysrhythmias with dopamine. For these reasons noted above, norepinephrine may be the initial agent for pharmaceutical support of shock, particularly in septic syndromes, with dopamine as a secondary or adjunct agent in patients at low risk for tachyarrhythmia or a relative bradycardia. ^{24, 56}

Dobutamine

Dobutamine is another adrenergic agonist that is similar to dopamine but with a greater effect on inotropic cardiac contractility due to a preferential action at b₁ receptors.⁶⁰ It can potentially induce peripheral vasodilatation due to its effect on arterial b₁ receptors.  Given this balance, dobutamine is an agent that should be utilized for cardiogenic shock when increased contractility is needed. These effects are particularly useful in patients with “wet and cold” heart failure who have a low cardiac output and volume-overloaded status.^{61, 62} However, it may be necessary to add another agent to provide additional peripheral vasoconstriction should the use of dobutamine affect lead to excessive vasodilatation.  

Epinephrine

One of the most powerful vasoactive agents, epinephrine has a high affinity for all b₁, b₂ and a₁ receptors.⁶³ These combined effects lead to increased cardiac output and improved BP by increasing cardiac contractility and peripheral vasoconstriction. The effect of epinephrine in limiting mast cell release of histamine makes it the preferred choice for the treatment of anaphylaxis.⁶⁴ However, side effects of epinephrine include hypertension, tachydysrhythmias, tissue ischemia from vigorous vasoconstriction, and induced lactic acidosis.⁶³

Phenylephrine

Phenylephrine is an a-adrenergic agonist that activates a₁ receptors on arteriole smooth muscle, resulting in vasoconstriction.⁶⁵ It is currently recommended only for hypotension related to procedural sedation.⁴⁷ Phenylephrine is not recommended for treating patients with septic shock, except when there are concerns about tachydysrhythmias; persistent hypotension with a high cardiac output after treatment with other vasoconstrictor and inotropic drugs; or when a “pure” vasoconstrictor may be preferred.^24,56,65

Summary

Although there are many other vasoactive agents that can be used, the selected agents discussed above represent those most commonly used in the ED. All demonstrate significant crossover effects and receptor activation, as well as impact on cardiac contractility and vasoconstriction. The suggested specific indications for each agent are based on current evidenced-based medicine, clinical guidelines, and theoretical benefits on clinical scenarios. But, as always, clinical decisions should be individualized for critically ill patients.

Conclusion

The resuscitation and initiation of care for critically ill patients must typically be immediately upon their arrival in the ED. While general guidelines or recommendations exist for commonly encountered pathologies, treatment should always be patient-centered, based on the needs and nuances unique to each patient in this vulnerable population. The initiation of mechanical ventilation, treatment of sepsis, management of hypertensive neurosurgical emergencies, and use of pressors in shock states are among the most critically important tasks an EP is called upon to perform. This review of current evidence-based guidelines and recommendations will help EPs provide the appropriate and unique care each patient requires.

Dr Brubaker is a resident in the department of emergency medicine at the University of Pittsburgh, Pennsylvania. Dr Yu is a fellow of adult critical care medicine – emergency medicine in the department of critical care medicine, University of Pittsburgh Medical Center, Pennsylvania. Dr Goodmanson is a resident in the department of emergency medicine at the University of Pittsburgh, Pennsylvania. Dr Schott is an assistant professor, department of emergency medicine and critical care medicine; assistant director of ultrasonography; director, critical care elective student rotation; and director, point of care ultrasound elective student rotation, at the University of Pittsburgh, Pennsylvania

Emergency medicine and critical care medicine share a responsibility for the care of acutely ill patients with life-threatening pathologies. The skills required of both emergency physicians (EPs) and critical care specialists to recognize, diagnose, and resuscitate such patients have resulted in many shared guidelines, recommendations, and publications. When critically ill patients enter the hospital through the ED, the care provided by EPs greatly impacts both the early and long-term outcomes. It is not uncommon for critically ill patients to spend several hours under the care of an EP while awaiting an available inpatient bed in the intensive care unit (ICU) or “step down” monitored unit. 

This article provides a summary review of current guidelines, evidence-based medicine recommendations, and the results of recent trials involving ventilator management, treatment of sepsis, management of hypertension accompanying neurological emergencies, and the selection of pressors for the treatment of different shock states. 

Ventilator Management

Mechanical ventilation is frequently undertaken in the ED for patients with respiratory failure—the origin of which is not always immediately clear. Data from the National Heart, Lung, and Blood Institute’s (NHLBI) acute respiratory distress syndrome (ARDS) clinical network (http://www.ardsnet.org) and other clinical trials have established the benefit of low tidal-volume, “lung-protective” ventilation in the patient with ARDS.^1,2 Numerous studies have also shown the benefit of low-tidal-volume (TV), ventilation in patients without ARDS, and its use is now the standard of care for a large range of respiratory conditions causing compromise.³

The prompt initiation of lung-protective ventilation has a significant impact on reducing ICU mortality.⁴ A recent retrospective review of 3.5 million ED visits showed the median length of stay for patients started on mechanical ventilation in the ED to be greater than 3 hours.⁵ Such a length of time on mechanical ventilation in this setting can have significant effects on the course of illness; however, it is not clear whether mechanical ventilation performed in the ED typically conforms to evidence-based standards. In one study performed in an academic center, less than one-third of patients with sepsis and respiratory failure received low-volume ventilation in the ED.⁶ Another study suggested that emergency medicine residents may not receive as much dedicated education on the initial management of ventilators as needed—despite the potentially unforgiving physiologic process of positive-pressure mechanical ventilation.⁷

The fundamental principles required to safely manage most patients in respiratory failure are not difficult to master. There are several simple evidence-based ventilator strategies for managing patients with respiratory failure. The three primary principles of initiating and providing effective mechanical ventilation are: (1) avoiding traumatic ventilation; (2) maintaining normoxia; and (3) maintaining appropriate acid-base balance. Each of these principles can be achieved in a stepwise fashion.

Step I: Establishing Lung-Protective Settings on the Ventilator

Three central parameters must be selected at the initiation of assist-control mechanical ventilation: TV, respiratory rate (RR), and positive end-expiratory pressure (PEEP). These parameters have been extensively studied, and there is excellent evidence to guide the EP in choosing the correct settings.

Tidal Volume. Although the normal human lung can accommodate about 6 L of air, in cases of respiratory failure, the surface area available for gas exchange is significantly reduced due to a pathologic process undermining entire regions of the air-blood interface. Consequently, a person whose normal lungs are suddenly required to perform the life-sustaining gas exchanges in critical illness with the much smaller lung surface is at a significant disadvantage.

The widely accepted lung-protective volumes range from 6 to 8 mL/kg of predicted body weight (PBW), a height-based calculation.⁸ For example, in a 6-foot tall man, 6 mL/kg of PBW amounts to a TV of 466 mL; in a 5-foot tall woman, the same amount of PBW amounts to a TV of 273 mL. Volumes may be referenced using PBW tables from the NHLBI ARDS network or by employing the following equations:

Adult men: PBW (kg) = 50 + 2.3 (height [in] – 60)

Adult women: PBW (kg) = 45.5 + 2.3 (height [in] – 60).⁹

Respiratory Rate. The RR should be set somewhat higher than normal because the TV per breath has been slightly reduced, and also because sick patients in a catabolic state may have larger minute ventilations than they would when healthy. As previously described, since the TV is restricted, RR is the most mobile parameter in maintaining appropriate minute ventilation. Minute ventilation (MV) is the product of RR multiplied by TV (MV = RR x TV), and this should be calculated to approximate the patient’s own efforts, which are dependent upon the clinical circumstances. For example, patients whose bodies are trying to compensate for an acidosis will require much higher rates than those who are simply obtunded and intubated for airway protection. In other words, in order to remove carbon dioxide (CO₂) in an acidemic patient, a higher RR rate may be required, whereas a lower rate may be selected to compensate for alkalemia while maintaining appropriate oxygen (O₂) levels in both cases.¹⁰

Positive End-Expiratory Pressure. Previous recommendations for ventilation in respiratory failure called for large TVs (ie, 10 to 15 mL/kg), partly out of concern that smaller volumes would promote distal airway collapse, thereby increasing the amount of lung that received blood but not air, consequently worsening overall oxygenation.¹¹ Although administering such large volumes has clearly proved harmful, the valid concern about distal airway collapse can be addressed in part by adjustments to PEEP, which acts to “stent” open airways after most of the tidal breath has left the airways.

Positive end-expiratory pressure, however, is not without risks.¹² Blood from the rest of the body will encounter resistance returning to a thoracic cavity persistently inflated by positive pressure, and this decrease in preload may contribute to hypotension. Similarly, a weak right ventricle may struggle to push blood into the compressed pulmonary vasculature, increasing the cardiac workload and further compromising hemodynamics.¹³ In general, PEEP should be set as low as the maintenance of adequate oxygenation permits. The NHLBI ARDS guidelines provide a table on balancing PEEP and the fraction of inspired O₂ (FiO₂), as well as hypotension, in refractory hypoxemic patients—with the limitation on PEEP set by the patients’ pulmonary compliance (plateau pressures, discussed next).⁸

After making these selections, several parameters must be monitored closely.  Those most relevant to lung-protective ventilation are the peak airway pressure and, most importantly, the plateau pressure. Numerous animal studies now demonstrate serious lung injury in both healthy and diseased lungs from high peak pressures (defined as a plateau pressure >30 cm water [H₂O]).^14,15 A high-pressure alarm sounding on the ventilator must be promptly addressed by an evaluation for easily reversible causes, such as tube obstruction, pneumothorax, breath stacking, pulmonary edema, or pleural effusions. A full discussion of the causes of elevated peak and plateau pressures is beyond the scope of this review, but if the plateau pressures remain consistently high, a reduction in TV may be necessary.

Step II: Maintaining Normoxia

As a severely hypoxic patient will rapidly decompensate with progression to death, a host of monitoring devices are used to alert the nurse or physician that O₂ levels have fallen below the normal range. Strategies to manage refractory hypoxia in the ventilated patient are complex. For most patients, 100% FiO₂ is initiated immediately after intubation to increase the safety of the procedure, but there is animal evidence that high O₂ levels promote inflammatory responses, and human data suggest hyperoxia can be deleterious to long-term outcomes, particularly following cardiac arrest and stroke.^16,17 A persistent O₂ saturation of 100% on pulse oximetry or a supraphysiologic partial pressure of O₂ (PaO₂) on an arterial blood gas (defined as >200 mm Hg) may actually cause the patient more harm than good. Therefore, the fraction of inspired O₂ should be titrated to maintain normoxia. The ARDS protocol, for example, targets an O₂ saturation of 88% to 95% and a PaO₂ of 55 to 80 mm Hg.⁸

Step III: Maintaining Acid-Base Balance

The basic principles of acid-base physiology should be familiar to EPs. When a patient is sedated and the airway secured, the primary means by which blood pH is maintained is now in the hands of the intubating physician. Patients with respiratory failure may have compensated for a preexisting derangement in their blood pH. If the preexisting condition is not recognized and ventilator settings are not maintained appropriately, they may be vulnerable to developing another derangement. Even on settings that allow the patient to breathe over a set rate, the sedation required to tolerate an endotracheal tube may cause significant respiratory depression, making it impossible for the patient to auto-regulate the respiratory component of acid-base homeostasis (ie, by hyperventilation). 

As in the discussion of RR, TVs are “fixed” based on low-TV lung-protective ventilation. Therefore, changing the patient’s set RR is the easiest method to adjust the partial pressure of CO₂ (PaCO₂), and consequently address any respiratory acidosis. An increase in the RR will increase the patient’s minute ventilation, leading to a decrease in serum PaCO₂ levels, whereas a decrease in the RR will have the converse effect. It is important to obtain an arterial blood-gas reading shortly after intubation and to continue to monitor the impact of any ventilator titrations on the patient’s acid-base status.

Studies of “permissive hypercapnia” in ARDS patients have shown that prioritizing lung-protective ventilator settings, even at the expense of a normal CO₂, reduce mortality.^1,18 Even in situations where it is not necessary to maintain hypercapnia for lung-protective settings, the hypercapnia appears to have beneficial effects.^19-21 No upper limits on hypercapnia have been established, and even extreme levels have been associated with successful patient outcomes.²² However, a study by Hickling et al²³ demonstrated that an initial trial of lung-protective ventilation demonstrated benefit from unbuffered hypercarbia and acidosis, reporting an average CO₂ level of 66 and a pH of 7. These guidelines should be appropriate for use in the ED.

In summary, assuming control of a patient’s respiratory system—with its nuanced and responsive role in acid-base, oxygenation, and cardiopulmonary hemodynamics—is one of the most difficult situations routinely encountered by an EP. While the procedure itself may be life-saving, the next several hours can have significant impact on the patient’s long-term outcome.

Treating Sepsis and Surviving Sepsis: Recommendations Versus the ARISE/ProCESS Trials

Sepsis and Septic Shock

Sepsis is defined as an infection plus systemic inflammatory response syndrome (SIRS). Severe sepsis is sepsis plus sepsis-induced organ dysfunction or tissue hypoperfusion resulting in or caused by lactic acidosis, acute lung injury, altered mental status, or coagulation abnormalities. Septic shock refers to persistent sepsis-induced hypotension despite adequate fluid resuscitation.²⁴ The ambiguity of these definitions may invariably lead to a practitioner’s underappreciation or misconception of the importance of sepsis.

Sepsis is one of the most common, yet least-recognized, entities. In the United States, it is estimated that 3 in 1,000 people annually are affected by sepsis, and every few seconds, a person dies of sepsis.²⁵ Both numbers underestimate the effects on the elderly. Clinical manifestations of sepsis vary, and the condition may originate from both community-acquired and healthcare-associated sources.

In 2001, a landmark study demonstrated that early goal-directed therapy (EGDT) reduced mortality and improved patient outcomes in patients presenting to the ED in severe sepsis.²⁶ The estimated 12% to 16% reduction in mortality reported in this trial began an initiative to broaden the scope and awareness of sepsis.

Current Literature and Evidence-Based Guidelines

The most recent guidelines for the management of septic shock from the Surviving Sepsis Campaign are summarized in Table 1. With its last revision, the Surviving Sepsis guidelines of 2012 has two main management foci—initiating treatment within the first 3 and the first 6 hours after recognition within the first 3 hours and those within the first 6 hours after sepsis recognition (Table 2). Within the first 3 hours, the treatment team should draw a serum lactate level; obtain cultures prior to the administration of antibiotics; initiate broad-spectrum antibiotics as early as possible; and administer 20 to 30 mL/kg of crystalloid fluids in patients with hypotension or a lactate level greater than 4 mmol/L. Within the first 6 hours, the clinician should administer intravenous (IV) vasopressors, preferentially norepinephrine, for persistent hypotension after a fluid challenge to maintain a mean arterial pressure >65 mm Hg; place a supra-diaphragmatic central venous catheter to measure a serum mixed venous O₂ saturation (ScvO₂) and central venous pressure (CVP); and measure serial serum lactate levels if they were initially elevated (lactate ≥4 mmol/L [36 mg/dL]).^24,30,31 The targets for ScvO₂ and CVP are ≥70%, and >8 mm Hg, respectively.

Summary

Sepsis is a prevalent ED presentation associated with mortality that can present in a complex fashion. Early recognition and management is essential and can be condensed into a few key recommendations. Becoming familiar with and incorporating these recommendations into daily practice will enable EPs to deliver quality care to every patient presenting with sepsis, and will also reduce mortality.

Blood Pressure Management for Select Neurological Emergencies

Patients with ischemic stroke, spontaneous intracerebral hemorrhage (ICH), and aneurysmal subarachnoid hemorrhage (SAH) often present with elevated blood pressures (BPs).^34-36 In caring for these patients, EPs face the question of how, or even if, the patient’s BP should be managed. What are the appropriate BP targets for each of the aforementioned pathologies? Does aggressive BP management benefit or harm the patient?

Background

The relationship between hypertension and stroke is different for each stroke type. Retrospective data show a U-shaped relationship between BP and mortality in ischemic stroke, with the highest mortality observed at both extremes of the BP curve.³⁴ Data also suggest increased mortality when ICH is accompanied by hypertension.³⁵ Hypertension may also be associated with a higher risk of rebleeding in patients with SAH due to aneurysms.³⁶ Because of the variable relationship between stroke and hypertension, therapeutic recommendations for each type of stroke can be confusing.

Current Literature and Evidence-Based Guidelines

Firm evidence to make therapeutic recommendations remains elusive. The recent American Heart Association (AHA) guidelines covering ischemic stroke, ICH, and SAH were published between late 2010 and early 2013, and several trials investigating the role of BP control in ischemic and hemorrhagic stroke have subsequently been published.^37-41

When the Cochrane Collaboration updated its systematic review on vasoactive medications in stroke in 2014 to include recent evidence,⁴² it ultimately concluded that lowering BP does not improve mortality, neurological deterioration, or quality of life regardless of stroke type, and suggest that further investigations should be undertaken.⁹ However, the Cochrane authors noted that two recent trials showed a statistically significant association between improved quality of life and BP reduction within 6 hours of stroke onset.^38-39 Although the data were compiled from just 2,835 patients of the 15,432 included in the entire Cochrane review, it suggested that interventions initiated in the ED may contribute to any potential beneficial outcomes from intensive BP control.

Ischemic Stroke

The China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) investigated the initiation of BP-control measures within 48 hours of onset of ischemic stroke in approximately 4,000 patients and found no significant difference in death or disability between the group that received BP-control interventions and the group that did not.³⁷ The Rapid Intervention With Glyceryl Trinitrate in Hypertensive Stroke Trial (RIGHT) included patients with both ischemic and hemorrhagic strokes. Though it studied only 41 patients, this trial suggests that early BP control is safe and may be associated with lower disability.³⁸ These findings are bolstered by the more recent Efficacy of Nitric Oxide in Stroke (ENOS) trial showing a similar safety profile for BP control in both ischemic and hemorrhagic strokes, though the mean difference in systolic BP after therapy was a mere 7 mm Hg.⁴⁰ The combined data from the RIGHT and ENOS trials offer little to clarify the question of appropriate BP control.

For now, the EP is left with the AHA/American Stroke Association (ASA) guideline’s recommendation “not to lower the BP during the initial 24 hours of acute ischemic stroke unless the BP is greater than 220/120 mm Hg.”³⁴ The recommendation differs in cases when a patient receives thrombolytics and hemorrhagic transformation is a risk. There have been no new data to change the AHA/ASA’s recommendations for patients receiving thrombolytics. In such cases, the EP should ensure the patient’s BP is below 185/110 mm Hg prior to thrombolytic administration and below 180/105 mm Hg during therapy.³⁴ A variety of agents is available to lower BP in this situation, and includes IV labetalol, nicardipine, esmolol, and others.

Intracerebral Hemorrhage

The recent literature on blood pressure control in ICH has also increased since the most recent AHA/ASA recommendations. The Second Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT-2 included over 2,800 patients randomized to intensive early therapy to reduce BP to less than 140 mm Hg or less than 180 mm Hg and found no significant difference in mortality or safety between the two groups, though intensive therapy was associated with less disability.³⁹ The Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial (ICH-ADAPT) trial further clarified the issue of safety during intensive BP control by showing no decrease in perihematomal cerebral blood flow in patients whose BP control was targeted to less than 150 mm Hg compared to those whose BP was less than 180 mm Hg, suggesting that aggressive BP reduction does not cause iatrogenic ischemic stroke.⁴¹

These combined data suggest that intensive BP management is safe for patients with ICH, providing reassurance for the AHA/ASA guideline recommendation that “in patients…with a systolic BP of 150 to 220 mm Hg, acute lowering of systolic BP to 140 mm Hg is probably safe.”³⁵ Whether this improves patient outcomes remains unclear. Again, multiple agents are available for BP control, including IV labetalol or nicardipine, with no agent identified as superior in producing better patient outcomes. A continuous infusion is recommended if several boluses are ineffective in achieving and maintaining the target BP, as BP variability has been associated with poorer outcomes.⁴³

Subarachnoid Hemorrhage

There are no large recent studies in the literature on antihypertensive therapy in SAH. The AHA/ASA guidelines updated in 2012 reflect the consensus that elevated BPs are associated with increased risk of aneurysmal rebleeding and thus poorer patient-oriented outcomes. The consensus remains to use a titratable agent to target a systolic BP less than 160 mm Hg until definitive neurosurgical therapy, such as aneurysmal coiling or clipping.³⁶ Given the variability of the sodium nitroprusside dose-response relationship, IV labetalol, and nicardipine, are  recommended agents for continuous control, though data showing differences in mortality and/or disability are lacking.³⁶ Again, retrospective data suggest that BP variability negatively impacts mortality and disability, so consider early initiation of continuous infusions to achieve and maintain consistency in the chosen target.⁴⁴

Summary

Pressors in the Management of Hypotension

Norepinephrine

Norepinephrine is one of the most commonly used agents for shock in the ED, with indications spanning multiple etiologies. It is an endogenous neurotransmitter that works predominantly on a₁ receptors as well as exerting some modest effects on b₁ and b₂ receptors, for combined vasopressor and improved cardiac contractility effect.^46-47 Norepinephrine is currently the recommended initial agent for sepsis-induced tissue hypoperfusion.²⁴ However, a recent Cochrane systematic review and meta-analysis supports evidence of limited differences among various pressors.⁴⁸ Several comparative randomized control trials show norepinephrine is as effective as other agents, but with fewer side effects.^24,49 With the ease and familiarity of its use by most EPs, and a wide therapeutic index for targeted effect versus arrhythmias, norepinephrine is a reasonable choice as the initial pressor in managing a wide variety of shock syndromes.

Vasopressin

Another commonly used agent in the treatment of shock, vasopressin is an analogue of the antidiuretic hormone secreted from the posterior pituitary gland, exerting its CV effects primarily as a vasoconstrictor by increasing intracellular calcium.⁵⁰ Vasopressin doses are 0.03 or 0.04 U/min IV without titration.^24,50 Early studies of septic patients demonstrated a relative deficiency of serum vasopressin levels, leading clinicians to utilize it in the treatment of sepsis-induced shock. However, the Vasopressin and Septic Shock Trial (VASST) trial demonstrated that the addition of vasopressin to norepinephrine did not produce any improvements in morbidity or mortality compared with norepinephrine alone.⁵¹ Despite these findings, vasopressin is still commonly used as a secondary agent to correct continued hypotension. Vasopressin may be appropriate for patients who specifically require peripheral vasoconstriction in the setting of good cardiac output and volume status, ability to tolerate increases in afterload, or in patients at risk for dysrhythmias.

Dopamine

Dopamine had been previously recommended as the initial choice of pharmacologic support for the management of shock.^24,52-54 Dopamine is an adrenergic agonist agent that works via a₁ and b₁ receptors as well as a precursor to the synthesis of norepinephrine and epinephrine.⁵⁵ There are dose-dependent effects on various receptors from escalating amounts administered,^55-56  but the literature does not support the concept of “renal-dose” dopamine.^57-59 A study by DeBaker et al⁴⁹ suggested no difference in efficacy between dopamine and norepinephrine, but demonstrated a greater tendency toward cardiac dysrhythmias with dopamine. For these reasons noted above, norepinephrine may be the initial agent for pharmaceutical support of shock, particularly in septic syndromes, with dopamine as a secondary or adjunct agent in patients at low risk for tachyarrhythmia or a relative bradycardia. ^{24, 56}

Dobutamine

Dobutamine is another adrenergic agonist that is similar to dopamine but with a greater effect on inotropic cardiac contractility due to a preferential action at b₁ receptors.⁶⁰ It can potentially induce peripheral vasodilatation due to its effect on arterial b₁ receptors.  Given this balance, dobutamine is an agent that should be utilized for cardiogenic shock when increased contractility is needed. These effects are particularly useful in patients with “wet and cold” heart failure who have a low cardiac output and volume-overloaded status.^{61, 62} However, it may be necessary to add another agent to provide additional peripheral vasoconstriction should the use of dobutamine affect lead to excessive vasodilatation.  

Epinephrine

One of the most powerful vasoactive agents, epinephrine has a high affinity for all b₁, b₂ and a₁ receptors.⁶³ These combined effects lead to increased cardiac output and improved BP by increasing cardiac contractility and peripheral vasoconstriction. The effect of epinephrine in limiting mast cell release of histamine makes it the preferred choice for the treatment of anaphylaxis.⁶⁴ However, side effects of epinephrine include hypertension, tachydysrhythmias, tissue ischemia from vigorous vasoconstriction, and induced lactic acidosis.⁶³

Phenylephrine

Phenylephrine is an a-adrenergic agonist that activates a₁ receptors on arteriole smooth muscle, resulting in vasoconstriction.⁶⁵ It is currently recommended only for hypotension related to procedural sedation.⁴⁷ Phenylephrine is not recommended for treating patients with septic shock, except when there are concerns about tachydysrhythmias; persistent hypotension with a high cardiac output after treatment with other vasoconstrictor and inotropic drugs; or when a “pure” vasoconstrictor may be preferred.^24,56,65

Summary

Although there are many other vasoactive agents that can be used, the selected agents discussed above represent those most commonly used in the ED. All demonstrate significant crossover effects and receptor activation, as well as impact on cardiac contractility and vasoconstriction. The suggested specific indications for each agent are based on current evidenced-based medicine, clinical guidelines, and theoretical benefits on clinical scenarios. But, as always, clinical decisions should be individualized for critically ill patients.

Conclusion

The resuscitation and initiation of care for critically ill patients must typically be immediately upon their arrival in the ED. While general guidelines or recommendations exist for commonly encountered pathologies, treatment should always be patient-centered, based on the needs and nuances unique to each patient in this vulnerable population. The initiation of mechanical ventilation, treatment of sepsis, management of hypertensive neurosurgical emergencies, and use of pressors in shock states are among the most critically important tasks an EP is called upon to perform. This review of current evidence-based guidelines and recommendations will help EPs provide the appropriate and unique care each patient requires.

Dr Brubaker is a resident in the department of emergency medicine at the University of Pittsburgh, Pennsylvania. Dr Yu is a fellow of adult critical care medicine – emergency medicine in the department of critical care medicine, University of Pittsburgh Medical Center, Pennsylvania. Dr Goodmanson is a resident in the department of emergency medicine at the University of Pittsburgh, Pennsylvania. Dr Schott is an assistant professor, department of emergency medicine and critical care medicine; assistant director of ultrasonography; director, critical care elective student rotation; and director, point of care ultrasound elective student rotation, at the University of Pittsburgh, Pennsylvania

Surgery involves a certain degree of risk. The risk could be in the form of a complication, or it could be surgical failure. When I was a resident, gynecologic oncologist Gary Johnson, MD, used to say: “If you don’t want complications, don’t do surgery.” I was never sure whether he was trying to make me feel better when complications occurred, or was just stating the facts. Maybe both. It could be argued that one should consider offering medical options before exposing a patient to surgical risks.

In this article, I review three recent studies that shed some light on patient selection for surgical intervention—more specifically, on surgical and counseling ­failures ­associated with surgical management of abnormal uterine bleeding (AUB):

Don’t resort to surgery until alternative treatments have been exhausted

Corona LE, Swenson CW, Sheetz KH, et al. Use of other treatments before hysterectomy for benign conditions in a statewide hospital collaborative [published online ahead of print December 23, 2014]. Am J Obstet Gynecol. pii: S0002-9378(14)02355-2. doi: 10.1016/j.ajog.2014.11.031.

In this analysis, Corona and colleagues evaluated the use of alternative treatments among women who underwent hysterectomy for uterine fibroids, AUB, endometriosis, or pelvic pain at 52 hospitals participating in the Michigan Surgical Quality Collabo­rative in 2013. They also determined whether the pathology was “supportive” or “unsupportive” of the surgical indication.

A significant percentage of hysterectomies were performed with an indication of AUB or fibroids, or both (49.1%). A combination of pain, AUB, and/or fibroids was the indication in 48.1% of hysterectomies, and endometriosis and/or pain was listed in 9.2%.

In 37.7% of cases (n = 1,281), no offering of alternative treatments was documented.

Although endometrial ablation was offered to 44.1% of women younger than age 40, to 48.3% of women aged 40 to 50 years, and to 31.6% of women older than age 50, the conservative, nonsurgical option of a levonorgestrel intrauterine system (LNG-IUS) was offered in only 12.7%, 12.4%, and 9.3% of these cases, respectively.

Overall, the rate of unsupportive pathology was 18.3% (n = 621). That rate was higher in women younger than age 40, compared with those aged 40 to 50 and older than age 50 (37.8% vs 12.0% and 7.5%, respectively; P<.001).

These data suggest that a significant number of women with AUB associated with ovulatory dysfunction (AUB-O) undergo hysterectomy. The authors point out that the American College of Obstetricians and Gynecologists (ACOG) recommends medical therapy as a first-line therapy for AUB-O rather than surgical therapy.

What this EVIDENCE means for practice
Although AUB is a common indication for hysterectomy, conservative alternative therapies should be offered when appropriate. A particularly cost-effective and effective conservative therapy—the LNG-IUS—is underutilized and should be considered more often.

How to determine who is most likely to benefit from endometrial ablation

Wishall KM, Price J, Pereira N, et al. Postablation risk factors for pain and subsequent hysterectomy. Obstet Gynecol. 2014;124(5):904–910.

Smithling KR, Savella G, Raker CA, et al. Preoperative uterine bleeding pattern and risk of endometrial ablation failure. Am J Obstet Gynecol. 2014;211(5):556.e1–e6.

Endometrial ablation has been around a long time—likely since the 1930s. However, it was not until the 1980s that operative hysteroscopy and endometrial ablation became commonplace. As a result of new, more “automated” technology, five nonresectoscopic endometrial ablation techniques were introduced, starting with FDA approval of the thermal balloon device in 1997.

Initially, information on the feasibility of endometrial ablation was presented in the form of case reports. Efficacy and safety were studied through FDA trials, which yielded variable amenorrhea rates but relatively high satisfaction rates in the range of 85% to 95%. In the interim, we have learned more refined details about endometrial ablation as case reports of unintended consequences have cropped up and as this technology has reached a broader physician base. After almost two decades of experience with nonresectoscopic endometrial ablation devices, information on “failure”—ie, the need for additional treatment—is surfacing.

Over the past year, as we have increased adoption of the PALM-COEIN classification system for the causes of AUB in women of reproductive age, we also have gleaned more information about how endometrial ablation works in this context. In general, PALM (polyp, adenomyosis, leiomyoma, and malignancy/hyperplasia) represents lesions that can be seen but may not necessarily be the cause of bleeding. COEIN (coagulopathy, ovulatory dysfunction, endometrial factors, iatrogenic, and not yet classified) represents causes of bleeding that may not be visible.

Although endometrial ablation is ideally suited for women with AUB related to endometrial factors (AUB-E), two studies from 2014 provide insight into endometrial ablation performed when lesions are present within the PALM classification, such as polyps (AUB-P), adenomyosis (AUB-A), and leiomyomas (AUB-L), and in patients with COEIN conditions, such as ovulatory dysfunction (AUB-O) and AUB-E.

Findings of Wishall and colleagues
Three hundred women who underwent endometrial ablation were evaluated in regard to postoperative pain and the need for subsequent hysterectomy. A total of 270 women were available for follow-up in this retrospective cohort (10% lost to follow-up). Wishall and colleagues set out to identify prognostic factors that would put a woman at risk for post-ablation pain. Their secondary outcome was the rate of hysterectomy after ablation.

The study was limited to second-generation endometrial ablation devices, including the thermal balloon, microwave, circulating hot fluid, and bipolar radiofrequency devices.

Wishall and colleagues found that the risk of failure was the highest (a quadrupling) when uterine abnormalities such as leiomyomas, adenomyosis, a thickened endometrial stripe, or polyps were present (adjusted odds ratio [OR], 3.96; 95% confidence interval [CI], 1.25–12.56).

As in other series, 19% of women ultimately required hysterectomy. Twenty-three percent developed new or worsening pain after ablation. Risk factors for postablation pain included a history of dysmenorrhea (OR, 1.74) and tubal sterilization (OR, 2.06).

Findings of Smithling and colleagues
Investigators evaluated the records of 968 women with AUB who had undergone endometrial ablation, categorizing their preoperative bleeding patterns as either regular (presumed AUB-E) or irregular (presumed AUB-O). Of these women, 961 (99.3%) had undergone radiofrequency bipolar endometrial ablation.

Smithling and colleagues hypothesized that women with AUB-O would have a higher failure rate—defined as the need for reablation or subsequent hysterectomy—than women with AUB-E because endometrial ablation does not necessarily address the pathology that underlies AUB-O. However, they found no difference in treatment failure or the need for a subsequent gynecologic procedure between groups during the 3-year period after endometrial ablation. The rate of treatment failure was 16.4% in women with regular bleeding—essentially the same as the rate for women with irregular bleeding (17.6%; P = .7) Risk factors associated with failure included:

Although there was no difference in failure rates between the group with regular bleeding versus the group with irregular bleeding, Smithling and colleagues were careful to avoid interpreting this finding as a recommendation for endometrial ablation in women with AUB-O.

What this EVIDENCE means for practice
When endometrial ablation is performed to treat lesions such as polyps, adenomyosis, and leiomyomata, women are nearly four times more likely to require subsequent hysterectomy.

A history of dysmenorrhea yielded a 74% higher risk of developing postablation pain, and a history of tubal sterilization more than doubled the risk, compared with no history of dysmenorrhea or tubal sterilization.

Women who undergo endometrial ablation for presumed AUB-O and presumed AUB-E have similar failure rates.

Preoperative factors such as dysmenorrhea, prior tubal sterilization, and obesity were identified as risk factors for ablation failure.

The choice between endometrial ablation and hysterectomy for patients with AUB-O depends on an individualized assessment of risks and benefits, including evaluation of medical comorbidities.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Surgery involves a certain degree of risk. The risk could be in the form of a complication, or it could be surgical failure. When I was a resident, gynecologic oncologist Gary Johnson, MD, used to say: “If you don’t want complications, don’t do surgery.” I was never sure whether he was trying to make me feel better when complications occurred, or was just stating the facts. Maybe both. It could be argued that one should consider offering medical options before exposing a patient to surgical risks.

In this article, I review three recent studies that shed some light on patient selection for surgical intervention—more specifically, on surgical and counseling ­failures ­associated with surgical management of abnormal uterine bleeding (AUB):

Don’t resort to surgery until alternative treatments have been exhausted

Corona LE, Swenson CW, Sheetz KH, et al. Use of other treatments before hysterectomy for benign conditions in a statewide hospital collaborative [published online ahead of print December 23, 2014]. Am J Obstet Gynecol. pii: S0002-9378(14)02355-2. doi: 10.1016/j.ajog.2014.11.031.

In this analysis, Corona and colleagues evaluated the use of alternative treatments among women who underwent hysterectomy for uterine fibroids, AUB, endometriosis, or pelvic pain at 52 hospitals participating in the Michigan Surgical Quality Collabo­rative in 2013. They also determined whether the pathology was “supportive” or “unsupportive” of the surgical indication.

A significant percentage of hysterectomies were performed with an indication of AUB or fibroids, or both (49.1%). A combination of pain, AUB, and/or fibroids was the indication in 48.1% of hysterectomies, and endometriosis and/or pain was listed in 9.2%.

In 37.7% of cases (n = 1,281), no offering of alternative treatments was documented.

Although endometrial ablation was offered to 44.1% of women younger than age 40, to 48.3% of women aged 40 to 50 years, and to 31.6% of women older than age 50, the conservative, nonsurgical option of a levonorgestrel intrauterine system (LNG-IUS) was offered in only 12.7%, 12.4%, and 9.3% of these cases, respectively.

Overall, the rate of unsupportive pathology was 18.3% (n = 621). That rate was higher in women younger than age 40, compared with those aged 40 to 50 and older than age 50 (37.8% vs 12.0% and 7.5%, respectively; P<.001).

These data suggest that a significant number of women with AUB associated with ovulatory dysfunction (AUB-O) undergo hysterectomy. The authors point out that the American College of Obstetricians and Gynecologists (ACOG) recommends medical therapy as a first-line therapy for AUB-O rather than surgical therapy.

What this EVIDENCE means for practice
Although AUB is a common indication for hysterectomy, conservative alternative therapies should be offered when appropriate. A particularly cost-effective and effective conservative therapy—the LNG-IUS—is underutilized and should be considered more often.

How to determine who is most likely to benefit from endometrial ablation

Wishall KM, Price J, Pereira N, et al. Postablation risk factors for pain and subsequent hysterectomy. Obstet Gynecol. 2014;124(5):904–910.

Smithling KR, Savella G, Raker CA, et al. Preoperative uterine bleeding pattern and risk of endometrial ablation failure. Am J Obstet Gynecol. 2014;211(5):556.e1–e6.

Endometrial ablation has been around a long time—likely since the 1930s. However, it was not until the 1980s that operative hysteroscopy and endometrial ablation became commonplace. As a result of new, more “automated” technology, five nonresectoscopic endometrial ablation techniques were introduced, starting with FDA approval of the thermal balloon device in 1997.

Initially, information on the feasibility of endometrial ablation was presented in the form of case reports. Efficacy and safety were studied through FDA trials, which yielded variable amenorrhea rates but relatively high satisfaction rates in the range of 85% to 95%. In the interim, we have learned more refined details about endometrial ablation as case reports of unintended consequences have cropped up and as this technology has reached a broader physician base. After almost two decades of experience with nonresectoscopic endometrial ablation devices, information on “failure”—ie, the need for additional treatment—is surfacing.

Over the past year, as we have increased adoption of the PALM-COEIN classification system for the causes of AUB in women of reproductive age, we also have gleaned more information about how endometrial ablation works in this context. In general, PALM (polyp, adenomyosis, leiomyoma, and malignancy/hyperplasia) represents lesions that can be seen but may not necessarily be the cause of bleeding. COEIN (coagulopathy, ovulatory dysfunction, endometrial factors, iatrogenic, and not yet classified) represents causes of bleeding that may not be visible.

Although endometrial ablation is ideally suited for women with AUB related to endometrial factors (AUB-E), two studies from 2014 provide insight into endometrial ablation performed when lesions are present within the PALM classification, such as polyps (AUB-P), adenomyosis (AUB-A), and leiomyomas (AUB-L), and in patients with COEIN conditions, such as ovulatory dysfunction (AUB-O) and AUB-E.

Findings of Wishall and colleagues
Three hundred women who underwent endometrial ablation were evaluated in regard to postoperative pain and the need for subsequent hysterectomy. A total of 270 women were available for follow-up in this retrospective cohort (10% lost to follow-up). Wishall and colleagues set out to identify prognostic factors that would put a woman at risk for post-ablation pain. Their secondary outcome was the rate of hysterectomy after ablation.

The study was limited to second-generation endometrial ablation devices, including the thermal balloon, microwave, circulating hot fluid, and bipolar radiofrequency devices.

Wishall and colleagues found that the risk of failure was the highest (a quadrupling) when uterine abnormalities such as leiomyomas, adenomyosis, a thickened endometrial stripe, or polyps were present (adjusted odds ratio [OR], 3.96; 95% confidence interval [CI], 1.25–12.56).

As in other series, 19% of women ultimately required hysterectomy. Twenty-three percent developed new or worsening pain after ablation. Risk factors for postablation pain included a history of dysmenorrhea (OR, 1.74) and tubal sterilization (OR, 2.06).

Findings of Smithling and colleagues
Investigators evaluated the records of 968 women with AUB who had undergone endometrial ablation, categorizing their preoperative bleeding patterns as either regular (presumed AUB-E) or irregular (presumed AUB-O). Of these women, 961 (99.3%) had undergone radiofrequency bipolar endometrial ablation.

Smithling and colleagues hypothesized that women with AUB-O would have a higher failure rate—defined as the need for reablation or subsequent hysterectomy—than women with AUB-E because endometrial ablation does not necessarily address the pathology that underlies AUB-O. However, they found no difference in treatment failure or the need for a subsequent gynecologic procedure between groups during the 3-year period after endometrial ablation. The rate of treatment failure was 16.4% in women with regular bleeding—essentially the same as the rate for women with irregular bleeding (17.6%; P = .7) Risk factors associated with failure included:

Although there was no difference in failure rates between the group with regular bleeding versus the group with irregular bleeding, Smithling and colleagues were careful to avoid interpreting this finding as a recommendation for endometrial ablation in women with AUB-O.

What this EVIDENCE means for practice
When endometrial ablation is performed to treat lesions such as polyps, adenomyosis, and leiomyomata, women are nearly four times more likely to require subsequent hysterectomy.

A history of dysmenorrhea yielded a 74% higher risk of developing postablation pain, and a history of tubal sterilization more than doubled the risk, compared with no history of dysmenorrhea or tubal sterilization.

Women who undergo endometrial ablation for presumed AUB-O and presumed AUB-E have similar failure rates.

Preoperative factors such as dysmenorrhea, prior tubal sterilization, and obesity were identified as risk factors for ablation failure.

The choice between endometrial ablation and hysterectomy for patients with AUB-O depends on an individualized assessment of risks and benefits, including evaluation of medical comorbidities.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Surgery involves a certain degree of risk. The risk could be in the form of a complication, or it could be surgical failure. When I was a resident, gynecologic oncologist Gary Johnson, MD, used to say: “If you don’t want complications, don’t do surgery.” I was never sure whether he was trying to make me feel better when complications occurred, or was just stating the facts. Maybe both. It could be argued that one should consider offering medical options before exposing a patient to surgical risks.

In this article, I review three recent studies that shed some light on patient selection for surgical intervention—more specifically, on surgical and counseling ­failures ­associated with surgical management of abnormal uterine bleeding (AUB):

Don’t resort to surgery until alternative treatments have been exhausted

Corona LE, Swenson CW, Sheetz KH, et al. Use of other treatments before hysterectomy for benign conditions in a statewide hospital collaborative [published online ahead of print December 23, 2014]. Am J Obstet Gynecol. pii: S0002-9378(14)02355-2. doi: 10.1016/j.ajog.2014.11.031.

In this analysis, Corona and colleagues evaluated the use of alternative treatments among women who underwent hysterectomy for uterine fibroids, AUB, endometriosis, or pelvic pain at 52 hospitals participating in the Michigan Surgical Quality Collabo­rative in 2013. They also determined whether the pathology was “supportive” or “unsupportive” of the surgical indication.

A significant percentage of hysterectomies were performed with an indication of AUB or fibroids, or both (49.1%). A combination of pain, AUB, and/or fibroids was the indication in 48.1% of hysterectomies, and endometriosis and/or pain was listed in 9.2%.

In 37.7% of cases (n = 1,281), no offering of alternative treatments was documented.

Although endometrial ablation was offered to 44.1% of women younger than age 40, to 48.3% of women aged 40 to 50 years, and to 31.6% of women older than age 50, the conservative, nonsurgical option of a levonorgestrel intrauterine system (LNG-IUS) was offered in only 12.7%, 12.4%, and 9.3% of these cases, respectively.

Overall, the rate of unsupportive pathology was 18.3% (n = 621). That rate was higher in women younger than age 40, compared with those aged 40 to 50 and older than age 50 (37.8% vs 12.0% and 7.5%, respectively; P<.001).

These data suggest that a significant number of women with AUB associated with ovulatory dysfunction (AUB-O) undergo hysterectomy. The authors point out that the American College of Obstetricians and Gynecologists (ACOG) recommends medical therapy as a first-line therapy for AUB-O rather than surgical therapy.

What this EVIDENCE means for practice
Although AUB is a common indication for hysterectomy, conservative alternative therapies should be offered when appropriate. A particularly cost-effective and effective conservative therapy—the LNG-IUS—is underutilized and should be considered more often.

How to determine who is most likely to benefit from endometrial ablation

Wishall KM, Price J, Pereira N, et al. Postablation risk factors for pain and subsequent hysterectomy. Obstet Gynecol. 2014;124(5):904–910.

Smithling KR, Savella G, Raker CA, et al. Preoperative uterine bleeding pattern and risk of endometrial ablation failure. Am J Obstet Gynecol. 2014;211(5):556.e1–e6.

Endometrial ablation has been around a long time—likely since the 1930s. However, it was not until the 1980s that operative hysteroscopy and endometrial ablation became commonplace. As a result of new, more “automated” technology, five nonresectoscopic endometrial ablation techniques were introduced, starting with FDA approval of the thermal balloon device in 1997.

Initially, information on the feasibility of endometrial ablation was presented in the form of case reports. Efficacy and safety were studied through FDA trials, which yielded variable amenorrhea rates but relatively high satisfaction rates in the range of 85% to 95%. In the interim, we have learned more refined details about endometrial ablation as case reports of unintended consequences have cropped up and as this technology has reached a broader physician base. After almost two decades of experience with nonresectoscopic endometrial ablation devices, information on “failure”—ie, the need for additional treatment—is surfacing.

Over the past year, as we have increased adoption of the PALM-COEIN classification system for the causes of AUB in women of reproductive age, we also have gleaned more information about how endometrial ablation works in this context. In general, PALM (polyp, adenomyosis, leiomyoma, and malignancy/hyperplasia) represents lesions that can be seen but may not necessarily be the cause of bleeding. COEIN (coagulopathy, ovulatory dysfunction, endometrial factors, iatrogenic, and not yet classified) represents causes of bleeding that may not be visible.

Although endometrial ablation is ideally suited for women with AUB related to endometrial factors (AUB-E), two studies from 2014 provide insight into endometrial ablation performed when lesions are present within the PALM classification, such as polyps (AUB-P), adenomyosis (AUB-A), and leiomyomas (AUB-L), and in patients with COEIN conditions, such as ovulatory dysfunction (AUB-O) and AUB-E.

Findings of Wishall and colleagues
Three hundred women who underwent endometrial ablation were evaluated in regard to postoperative pain and the need for subsequent hysterectomy. A total of 270 women were available for follow-up in this retrospective cohort (10% lost to follow-up). Wishall and colleagues set out to identify prognostic factors that would put a woman at risk for post-ablation pain. Their secondary outcome was the rate of hysterectomy after ablation.

The study was limited to second-generation endometrial ablation devices, including the thermal balloon, microwave, circulating hot fluid, and bipolar radiofrequency devices.

Wishall and colleagues found that the risk of failure was the highest (a quadrupling) when uterine abnormalities such as leiomyomas, adenomyosis, a thickened endometrial stripe, or polyps were present (adjusted odds ratio [OR], 3.96; 95% confidence interval [CI], 1.25–12.56).

As in other series, 19% of women ultimately required hysterectomy. Twenty-three percent developed new or worsening pain after ablation. Risk factors for postablation pain included a history of dysmenorrhea (OR, 1.74) and tubal sterilization (OR, 2.06).

Findings of Smithling and colleagues
Investigators evaluated the records of 968 women with AUB who had undergone endometrial ablation, categorizing their preoperative bleeding patterns as either regular (presumed AUB-E) or irregular (presumed AUB-O). Of these women, 961 (99.3%) had undergone radiofrequency bipolar endometrial ablation.

Smithling and colleagues hypothesized that women with AUB-O would have a higher failure rate—defined as the need for reablation or subsequent hysterectomy—than women with AUB-E because endometrial ablation does not necessarily address the pathology that underlies AUB-O. However, they found no difference in treatment failure or the need for a subsequent gynecologic procedure between groups during the 3-year period after endometrial ablation. The rate of treatment failure was 16.4% in women with regular bleeding—essentially the same as the rate for women with irregular bleeding (17.6%; P = .7) Risk factors associated with failure included:

Although there was no difference in failure rates between the group with regular bleeding versus the group with irregular bleeding, Smithling and colleagues were careful to avoid interpreting this finding as a recommendation for endometrial ablation in women with AUB-O.

What this EVIDENCE means for practice
When endometrial ablation is performed to treat lesions such as polyps, adenomyosis, and leiomyomata, women are nearly four times more likely to require subsequent hysterectomy.

A history of dysmenorrhea yielded a 74% higher risk of developing postablation pain, and a history of tubal sterilization more than doubled the risk, compared with no history of dysmenorrhea or tubal sterilization.

Women who undergo endometrial ablation for presumed AUB-O and presumed AUB-E have similar failure rates.

Preoperative factors such as dysmenorrhea, prior tubal sterilization, and obesity were identified as risk factors for ablation failure.

The choice between endometrial ablation and hysterectomy for patients with AUB-O depends on an individualized assessment of risks and benefits, including evaluation of medical comorbidities.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Probiotics—live micoorganisms that are consumed as supplements or food for purported health benefits—are a popular over-the-counter remedy for various gastrointestinal (GI) ailments and other conditions, but the evidence supporting their use is mixed. Probiotics interact with the normal flora of the human body. They are believed to act by multiple mechanisms to deliver beneficial effects, including providing a protective barrier, altering intestinal pH to favor the growth of nonpathogenic bacteria, enhancing the host’s immunologic response, producing antimicrobial substances, and directly competing with pathogenic bacteria for receptors in the GI tract.¹ (See “The normal human intestinal flora.”)

In the United States, Lactobacillus and Bifidobacterium are the probiotic genera that are most commonly used. (For a list of the specific probiotic species found in 5 popular products, see TABLE 1.^2-6) The review that follows examines the evidence for using probiotics for select GI ailments, including several types of diarrheal illnesses, inflammatory bowel disease (Crohn’s disease and ulcerative colitis), and irritable bowel syndrome (IBS). These findings are summarized in TABLE 2.^1,7-21

Probiotics may help with some types of diarrhea

Acute infectious diarrhea. Viruses, bacteria, and parasites cause acute infectious diarrhea, and probiotics are thought to act against these pathogens by competing for available nutrients and pattern recognition receptors in the GI endothelium, acidifying the local environment, and increasing immune responses within the GI tract. In a meta-analysis of 63 studies (N=8014) that used multiple strains and dosages of probiotics, investigators found probiotics shortened the duration of acute infectious diarrhea by approximately 24 hours (95% confidence interval [CI], 15.9-33.6 hours).⁷ Probiotics also reduced both the risk of diarrhea lasting longer than 4 days (relative risk [RR]=0.41; 95% CI, 0.32-0.53) and stool frequency on Day 2 of illness (mean difference of 0.80 stools; 95% CI, 0.45-1.14).

Traveler’s diarrhea. The incidence of traveler’s diarrhea is >50% when traveling to high-risk areas such as the Middle East, North Africa, Latin America, and Southeast Asia, and 5% to 10% when traveling to areas such as North America, Northern Europe, the United Kingdom, Australia, and New Zealand.⁸ Traveler’s diarrhea may be caused by ingesting food and liquids contaminated with fecal material. Symptoms include diarrhea, cramps, and nausea that if untreated typically last from 2 to 6 days but can last for as long as a month.⁸

In a meta-analysis of 12 studies (N=5171) that evaluated various probiotic strains, researchers found probiotics effectively prevented traveler’s diarrhea in US and European travelers who visited a variety of vacation spots (pooled RR=0.85; 95% CI, 0.79-0.91).⁸ No serious adverse events were reported.

Radiation-induced diarrhea. Radiation treatments to the abdomen and pelvis can damage the lower GI tract and cause diarrhea. The pooled results from a meta-analysis that included 6 studies (N=1449) significantly favored the use of probiotics over placebo for decreasing the incidence of radiation-induced diarrhea (odds ratio [OR]=0.44; 95% CI, 0.21-0.92).⁹ Probiotics use also was associated with decreased loperamide use (OR=0.29; 95% CI, 0.01-6.80) and decreased incidence of watery stools (OR=0.36; 95% CI, 0.05-2.81), but these outcomes did not reach statistical significance.

Antibiotic-associated diarrhea. Antibiotic use has long been associated with the development of diarrheal illness, sometimes due to the acceleration of GI motility (eg, erythromycin) or by causing osmotic diarrhea by decreasing GI bacteria that assist in carbohydrate breakdown.¹¹ A meta-analysis that evaluated 63 randomized controlled trials (RCTs) (N=11,811) showed that probiotics are effective for treating and preventing antibiotic-associated diarrhea (AAD).¹ There was a statistically significant reduction in AAD among patients who received probiotics (RR=0.58; 95% CI, 0.50-0.68; number needed to treat [NNT]=13). Most of the studies in this meta-analysis used a Lactobacillus probiotic alone or in combination with another probiotic. Researchers did not analyze whether the efficacy varied by patient population, probiotic used, causative antibiotic, or duration of treatment.¹

Another meta-analysis of 34 studies (N=4138) also found probiotic therapy can prevent AAD.¹⁰ The pooled RR for AAD was 0.53 (95% CI, 0.44-0.63) for patients treated with probiotics compared to placebo, with an NNT of 8 (95% CI, 7-11). The effects remained significant when results were grouped by probiotic species, patient age, and duration of antibiotic treatment. Among a subgroup of patients in this meta-analysis who were being treated for Helicobacter pylori, the pooled RR of AAD was 0.37 (95% CI, 0.20-0.69) and the NNT was 5 (95% CI, 4-10).¹⁰ However, the 2013 PLACIDE trial (N=17,420) found no significant decrease in AAD rates in hospitalized patients over age 65 years being treated with antibiotics who received probiotics (RR=1.04; 95% CI, 0.84-1.28).²²

Clostridium difficile-associated diarrhea. As we know, antibiotics can disrupt the normal GI flora and permit overgrow of Clostridium difficile, which can result in C. difficile-associated diarrhea (CDAD).¹² This can occur with oral, parenteral, and even topical antibiotics.¹¹ Researchers have investigated whether probiotics can prevent this opportunistic C. difficile overgrowth.

A 2012 meta-analysis of 20 trials (N=38,180) found probiotic prophylaxis prevented CDAD in both inpatients and outpatients while not increasing the incidence of significant adverse effects.¹² Probiotics decreased the incidence of CDAD by 66% (pooled RR=0.34, 95% CI, 0.24-0.49).¹² Adverse events occurred in 9.3% of patients taking probiotics, compared with 12.6% of controls (RR=0.82, 95% CI, 0.65-1.05).¹²

Conversely, a 2008 review of 4 studies (N=336) concluded there is insufficient evidence for using probiotics to treat CDAD, either as monotherapy or adjunct therapy.¹¹ One trial in this meta-analysis (N=124) found patients who received the probiotic Saccharomyces boulardii in addition to antibiotic therapy were significantly less likely to experience CDAD recurrence than those who received placebo (RR=0.59; 95% CI, 0.35-0.98).¹¹ However, this benefit was not found in the other trials in this meta-analysis.¹¹

The PLACIDE trial found probiotics did not prevent CDAD in hospitalized patients over age 65 years; 0.8% of patients who received probiotics developed CDAD, compared to 1.2% in the placebo group (RR=0.71, 95% CI, 0.34-1.47).²²

Helicobacter pylori infection. The triple therapy regimen of a proton pump inhibitor plus the antibiotics clarithromycin and amoxicillin is the recommended treatment for H. pylori infection.¹³ Problems with this treatment include adverse effects such as diarrhea and decreased eradication rates, in part due to antibiotic resistance. Certain Lactobacillus species have been shown to inhibit or kill H. pylori in vitro,¹³ and evidence from several meta-analyses suggests probiotics should be an adjunct therapy when treating H. pylori.

In a meta-analysis of 10 RCTs (N=963), fermented milk-based probiotics improved H. pylori eradication rates by 5% to 15%.¹⁴ In another meta-analysis that evaluated 5 RCTs (N=1307), S. boulardii significantly increased the H. pylori eradication rate when used as an adjunct to triple therapy (RR=1.13; 95% CI, 1.05-1.21) and reduced the rate of treatment-related adverse effects (RR=0.46; 95% CI, 0.3-0.7).¹³ In a third meta-analysis of 10 trials (N=1469), Lactobacillus supplementation increased H. pylori eradication rates (OR=2.1; 95% CI, 1.4-3.1) while decreasing the overall incidence of adverse effects (OR=0.3; 0.1-0.8).¹⁵

For inflammatory bowel disease, probiotics are unlikely to help

Current therapies for Crohn’s disease and ulcerative colitis, such as corticosteroids and other immunosuppressive agents, are effective but have significant adverse events.¹⁸ Researchers explored whether probiotics might help treat these diseases by improving immune response, the balance of microbes in the GI tract, and the intestinal barrier.¹⁸

Crohn’s disease. In a meta-analysis that was able to identify only one small RCT (N=11), 80% of patients receiving probiotic treatment went into remission, compared to 83% in the placebo group (OR=0.80; 95% CI, 0.04–17.20).¹⁶ Researchers concluded there was insufficient evidence for the use of probiotics for inducing remission in Crohn’s disease.

Another meta-analysis of 7 small studies (N=160) found no significant evidence supporting probiotic use for maintaining remission in Crohn’s disease compared with aminosalicylates or azathioprine.¹⁷ One small study in this review found there was a benefit to combining S. boulardii with a reduced level of standard maintenance therapy when compared to standard therapy alone, but this difference was not statistically significant.¹⁷

Ulcerative colitis. A systematic review of 4 RCTs (N=244) that compared conventional treatment alone to conventional treatment plus probiotics for remission or clinical improvement in patients with active ulcerative colitis found no significant differences between groups.¹⁸ Another meta-analysis of 4 studies (N=587) found that compared to placebo or treatment with mesalazine, probiotics had no benefit for maintaining remission in ulcerative colitis.¹⁹ The rate of relapse was 40.1% in the probiotics group compared to 34.1% in the mesalazine group. The number of adverse effects was similar in both groups.

Most evidence suggests probiotics are useful for IBS

In RCTs, probiotic supplements—but not yogurt containing probiotics—reduced IBS symptoms. Research suggests that imbalances in GI flora, along with subsequent dysfunction in intestinal barriers and translocation of intestinal flora, may play a role in symptoms associated with IBS, such as abdominal pain, bloating, and diarrhea/constipation.²⁰ There are few effective therapeutic options for patients suffering with IBS.

In a systematic review of 19 RCTs (N=1650), probiotics were significantly more effective than placebo for patients with IBS, with an NNT of 4 (95% CI, 3-12.5).²¹ This review did not evaluate the difference between various probiotic species and strains.

In an RCT (N=122), the probiotic strain Bifidobacterium bifidum MIMBb75 was found to be safe and beneficial for treating IBS symptoms and improving patients’ quality of life.²⁰ On a 7-point scale of global assessment of IBS symptoms, the score was reduced by 0.88 points (95% CI, 0.69-1.07) in the group that received B. bifidum MIMBb75 and 0.16 points (95% CI, -0.32-0.00) in the placebo group (P<0.0001). Almost half (47%) of the patients who received B. bifidum MIMBb75 reported adequate relief, compared to 11% in the placebo group (P<.0001).

An RCT (N=179) that compared yogurt that contained probiotics to non-probiotic yogurt found the probiotic yogurt had no benefits for treating IBS symptoms.²³ After 4 weeks, 57% of patients who ate the probiotic yogurt reported adequate relief, compared to 53% of those who ate non-probiotic yogurt (P=0.71). After 8 weeks, those numbers were 47% and 68%, respectively.²³

CORRESPONDENCE
Erik R. Clauson, DO, Nellis Family Medicine Residency, 99 MDOS/SGOF, 4700 Las Vegas Boulevard North, Nellis Air Force Base, NV 89191; [email protected] 

REFERENCES

1. Hempel S, Newberry SJ, Maher AR, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. JAMA. 2012;307:1959-1969.

2. Procter & Gamble. Align product information. Procter & Gamble Align Web site. Available at: http://www.aligngi.com/information-on-Align-probiotic-supplement. Accessed February 13, 2015.

3. Bayer HealthCare. Phillip’s Colon Health product information. Bayer HealthCare Phillip’s Colon Health Web site. Available at: http://phillipspro.com/en/home/product-information/index.php. Accessed February 13, 2015.

4. Nature’s Bounty. Nature’s Bounty Acidophilus Probiotic product label. Nature’s Bounty Web site. Available at: http://images.vitaminimages.com/cdn/sd/pdf/L002610-NB.PDF. Accessed February 13, 2015.

5.  Dannon. Activia. Dannon Activia Web site. Available at: http://activia.us.com/probiotic-yogurt/activia. Accessed February 13, 2015.

6. Lifeway. Lifeway Kefir frequently asked questions. Lifeway Kefir Web site. Available at: http://lifewaykefir.com/faq/. Accessed February 13, 2015.

7. Allen SJ, Martinez EG, Gregorio GV, et al. Probiotics for treating acute infectious diarrhoea. Cochrane Database Syst Rev. 2010;(11):CD003048.

8. McFarland LV. Meta-analysis of probiotics for the prevention of traveler’s diarrhea. Travel Med Infect Dis. 2007;5:97-105.

9. Hamad A, Fragkos KC, Forbes A. A systemic review and meta-analysis of probiotics for the management of radiation induced bowel disease. Clin Nutr. 2013;32:353-360.

10. Videlock EJ, Cremonini F. Meta-analysis: probiotics in antibiotic-associated diarrhoea. Aliment Pharmacol Ther. 2012;35:1355-1369.

11. Pillai A, Nelson RL. Probiotics for treatment of Clostridium difficile-associated colitis in adults. Cochrane Database Syst Rev. 2008;(1):CD004611.

12. Johnston BC, Ma SY, Goldenberg JZ, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and meta-analysis. Ann Intern Med. 2012;157:878-888.

13. Szajewska H, Horvath A, Piwowarczyk A. Meta-analysis: the effects of Saccharomyces boulardii supplementation on Helicobacter pylori eradication rates and side effects during treatment. Aliment Pharmacol Ther. 2010;32:1069-1079.

14. Sachdeva A, Nagpal J. Effect of fermented milk-based probiotic preparations on Helicobacter pylori eradication: a systematic review and meta-analysis of randomized-controlled trials. Eur J Gastroenterol Hepatol. 2009;21:45-53.

15. Wang ZH, Gao QY, Fang JY. Meta-analysis of the efficacy and safety of Lactobacillus-containing and Bifidobacterium-containing probiotic compound preparation in Helicobacter pylori eradication therapy. J Clin Gastroenterol. 2013;47:25-32.

16. Butterworth AD, Thomas AG, Akobeng AK. Probiotics for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2008;16:CD006634.

17. Rolfe VE, Fortun PJ, Hawkey CJ, et al. Probiotics for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev. 2006;(4):CD004826.

18. Mallon P, McKay D, Kirk SJ, et al. Probiotics for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2007;(4):CD005573.

19. Naidoo K, Gordon M, Fagbemi AO, et al. Probiotics for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2011;(12):CD007443.

20. Guglielmetti S, Mora D, Gschwender M, et al. Randomised clinical trial: Bifidobacterium bifidum MIMBb75 significantly alleviates irritable bowel syndrome and improves quality of life–– a double-blind, placebo-controlled study. Aliment Pharmacol Ther. 2011;33:1123-1132.

21. Moayyedi P, Ford AC, Talley NJ, et al. The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review. Gut. 2010;59:325-332.

22. Allen SJ, Wareham K, Wang D, et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2013;382:1249-1257.

23. Roberts LM, McCahon D, Holder R, et al. A randomised controlled trial of a probiotic ‘functional food’ in the management of irritable bowel syndrome. BMC Gastroenterol. 2013;13:45.

Probiotics—live micoorganisms that are consumed as supplements or food for purported health benefits—are a popular over-the-counter remedy for various gastrointestinal (GI) ailments and other conditions, but the evidence supporting their use is mixed. Probiotics interact with the normal flora of the human body. They are believed to act by multiple mechanisms to deliver beneficial effects, including providing a protective barrier, altering intestinal pH to favor the growth of nonpathogenic bacteria, enhancing the host’s immunologic response, producing antimicrobial substances, and directly competing with pathogenic bacteria for receptors in the GI tract.¹ (See “The normal human intestinal flora.”)

In the United States, Lactobacillus and Bifidobacterium are the probiotic genera that are most commonly used. (For a list of the specific probiotic species found in 5 popular products, see TABLE 1.^2-6) The review that follows examines the evidence for using probiotics for select GI ailments, including several types of diarrheal illnesses, inflammatory bowel disease (Crohn’s disease and ulcerative colitis), and irritable bowel syndrome (IBS). These findings are summarized in TABLE 2.^1,7-21

Probiotics may help with some types of diarrhea

Acute infectious diarrhea. Viruses, bacteria, and parasites cause acute infectious diarrhea, and probiotics are thought to act against these pathogens by competing for available nutrients and pattern recognition receptors in the GI endothelium, acidifying the local environment, and increasing immune responses within the GI tract. In a meta-analysis of 63 studies (N=8014) that used multiple strains and dosages of probiotics, investigators found probiotics shortened the duration of acute infectious diarrhea by approximately 24 hours (95% confidence interval [CI], 15.9-33.6 hours).⁷ Probiotics also reduced both the risk of diarrhea lasting longer than 4 days (relative risk [RR]=0.41; 95% CI, 0.32-0.53) and stool frequency on Day 2 of illness (mean difference of 0.80 stools; 95% CI, 0.45-1.14).

Traveler’s diarrhea. The incidence of traveler’s diarrhea is >50% when traveling to high-risk areas such as the Middle East, North Africa, Latin America, and Southeast Asia, and 5% to 10% when traveling to areas such as North America, Northern Europe, the United Kingdom, Australia, and New Zealand.⁸ Traveler’s diarrhea may be caused by ingesting food and liquids contaminated with fecal material. Symptoms include diarrhea, cramps, and nausea that if untreated typically last from 2 to 6 days but can last for as long as a month.⁸

In a meta-analysis of 12 studies (N=5171) that evaluated various probiotic strains, researchers found probiotics effectively prevented traveler’s diarrhea in US and European travelers who visited a variety of vacation spots (pooled RR=0.85; 95% CI, 0.79-0.91).⁸ No serious adverse events were reported.

Radiation-induced diarrhea. Radiation treatments to the abdomen and pelvis can damage the lower GI tract and cause diarrhea. The pooled results from a meta-analysis that included 6 studies (N=1449) significantly favored the use of probiotics over placebo for decreasing the incidence of radiation-induced diarrhea (odds ratio [OR]=0.44; 95% CI, 0.21-0.92).⁹ Probiotics use also was associated with decreased loperamide use (OR=0.29; 95% CI, 0.01-6.80) and decreased incidence of watery stools (OR=0.36; 95% CI, 0.05-2.81), but these outcomes did not reach statistical significance.

Antibiotic-associated diarrhea. Antibiotic use has long been associated with the development of diarrheal illness, sometimes due to the acceleration of GI motility (eg, erythromycin) or by causing osmotic diarrhea by decreasing GI bacteria that assist in carbohydrate breakdown.¹¹ A meta-analysis that evaluated 63 randomized controlled trials (RCTs) (N=11,811) showed that probiotics are effective for treating and preventing antibiotic-associated diarrhea (AAD).¹ There was a statistically significant reduction in AAD among patients who received probiotics (RR=0.58; 95% CI, 0.50-0.68; number needed to treat [NNT]=13). Most of the studies in this meta-analysis used a Lactobacillus probiotic alone or in combination with another probiotic. Researchers did not analyze whether the efficacy varied by patient population, probiotic used, causative antibiotic, or duration of treatment.¹

Another meta-analysis of 34 studies (N=4138) also found probiotic therapy can prevent AAD.¹⁰ The pooled RR for AAD was 0.53 (95% CI, 0.44-0.63) for patients treated with probiotics compared to placebo, with an NNT of 8 (95% CI, 7-11). The effects remained significant when results were grouped by probiotic species, patient age, and duration of antibiotic treatment. Among a subgroup of patients in this meta-analysis who were being treated for Helicobacter pylori, the pooled RR of AAD was 0.37 (95% CI, 0.20-0.69) and the NNT was 5 (95% CI, 4-10).¹⁰ However, the 2013 PLACIDE trial (N=17,420) found no significant decrease in AAD rates in hospitalized patients over age 65 years being treated with antibiotics who received probiotics (RR=1.04; 95% CI, 0.84-1.28).²²

Clostridium difficile-associated diarrhea. As we know, antibiotics can disrupt the normal GI flora and permit overgrow of Clostridium difficile, which can result in C. difficile-associated diarrhea (CDAD).¹² This can occur with oral, parenteral, and even topical antibiotics.¹¹ Researchers have investigated whether probiotics can prevent this opportunistic C. difficile overgrowth.

A 2012 meta-analysis of 20 trials (N=38,180) found probiotic prophylaxis prevented CDAD in both inpatients and outpatients while not increasing the incidence of significant adverse effects.¹² Probiotics decreased the incidence of CDAD by 66% (pooled RR=0.34, 95% CI, 0.24-0.49).¹² Adverse events occurred in 9.3% of patients taking probiotics, compared with 12.6% of controls (RR=0.82, 95% CI, 0.65-1.05).¹²

Conversely, a 2008 review of 4 studies (N=336) concluded there is insufficient evidence for using probiotics to treat CDAD, either as monotherapy or adjunct therapy.¹¹ One trial in this meta-analysis (N=124) found patients who received the probiotic Saccharomyces boulardii in addition to antibiotic therapy were significantly less likely to experience CDAD recurrence than those who received placebo (RR=0.59; 95% CI, 0.35-0.98).¹¹ However, this benefit was not found in the other trials in this meta-analysis.¹¹

The PLACIDE trial found probiotics did not prevent CDAD in hospitalized patients over age 65 years; 0.8% of patients who received probiotics developed CDAD, compared to 1.2% in the placebo group (RR=0.71, 95% CI, 0.34-1.47).²²

Helicobacter pylori infection. The triple therapy regimen of a proton pump inhibitor plus the antibiotics clarithromycin and amoxicillin is the recommended treatment for H. pylori infection.¹³ Problems with this treatment include adverse effects such as diarrhea and decreased eradication rates, in part due to antibiotic resistance. Certain Lactobacillus species have been shown to inhibit or kill H. pylori in vitro,¹³ and evidence from several meta-analyses suggests probiotics should be an adjunct therapy when treating H. pylori.

In a meta-analysis of 10 RCTs (N=963), fermented milk-based probiotics improved H. pylori eradication rates by 5% to 15%.¹⁴ In another meta-analysis that evaluated 5 RCTs (N=1307), S. boulardii significantly increased the H. pylori eradication rate when used as an adjunct to triple therapy (RR=1.13; 95% CI, 1.05-1.21) and reduced the rate of treatment-related adverse effects (RR=0.46; 95% CI, 0.3-0.7).¹³ In a third meta-analysis of 10 trials (N=1469), Lactobacillus supplementation increased H. pylori eradication rates (OR=2.1; 95% CI, 1.4-3.1) while decreasing the overall incidence of adverse effects (OR=0.3; 0.1-0.8).¹⁵

For inflammatory bowel disease, probiotics are unlikely to help

Current therapies for Crohn’s disease and ulcerative colitis, such as corticosteroids and other immunosuppressive agents, are effective but have significant adverse events.¹⁸ Researchers explored whether probiotics might help treat these diseases by improving immune response, the balance of microbes in the GI tract, and the intestinal barrier.¹⁸

Crohn’s disease. In a meta-analysis that was able to identify only one small RCT (N=11), 80% of patients receiving probiotic treatment went into remission, compared to 83% in the placebo group (OR=0.80; 95% CI, 0.04–17.20).¹⁶ Researchers concluded there was insufficient evidence for the use of probiotics for inducing remission in Crohn’s disease.

Another meta-analysis of 7 small studies (N=160) found no significant evidence supporting probiotic use for maintaining remission in Crohn’s disease compared with aminosalicylates or azathioprine.¹⁷ One small study in this review found there was a benefit to combining S. boulardii with a reduced level of standard maintenance therapy when compared to standard therapy alone, but this difference was not statistically significant.¹⁷

Ulcerative colitis. A systematic review of 4 RCTs (N=244) that compared conventional treatment alone to conventional treatment plus probiotics for remission or clinical improvement in patients with active ulcerative colitis found no significant differences between groups.¹⁸ Another meta-analysis of 4 studies (N=587) found that compared to placebo or treatment with mesalazine, probiotics had no benefit for maintaining remission in ulcerative colitis.¹⁹ The rate of relapse was 40.1% in the probiotics group compared to 34.1% in the mesalazine group. The number of adverse effects was similar in both groups.

Most evidence suggests probiotics are useful for IBS

In RCTs, probiotic supplements—but not yogurt containing probiotics—reduced IBS symptoms. Research suggests that imbalances in GI flora, along with subsequent dysfunction in intestinal barriers and translocation of intestinal flora, may play a role in symptoms associated with IBS, such as abdominal pain, bloating, and diarrhea/constipation.²⁰ There are few effective therapeutic options for patients suffering with IBS.

In a systematic review of 19 RCTs (N=1650), probiotics were significantly more effective than placebo for patients with IBS, with an NNT of 4 (95% CI, 3-12.5).²¹ This review did not evaluate the difference between various probiotic species and strains.

In an RCT (N=122), the probiotic strain Bifidobacterium bifidum MIMBb75 was found to be safe and beneficial for treating IBS symptoms and improving patients’ quality of life.²⁰ On a 7-point scale of global assessment of IBS symptoms, the score was reduced by 0.88 points (95% CI, 0.69-1.07) in the group that received B. bifidum MIMBb75 and 0.16 points (95% CI, -0.32-0.00) in the placebo group (P<0.0001). Almost half (47%) of the patients who received B. bifidum MIMBb75 reported adequate relief, compared to 11% in the placebo group (P<.0001).

An RCT (N=179) that compared yogurt that contained probiotics to non-probiotic yogurt found the probiotic yogurt had no benefits for treating IBS symptoms.²³ After 4 weeks, 57% of patients who ate the probiotic yogurt reported adequate relief, compared to 53% of those who ate non-probiotic yogurt (P=0.71). After 8 weeks, those numbers were 47% and 68%, respectively.²³

CORRESPONDENCE
Erik R. Clauson, DO, Nellis Family Medicine Residency, 99 MDOS/SGOF, 4700 Las Vegas Boulevard North, Nellis Air Force Base, NV 89191; [email protected] 

REFERENCES

1. Hempel S, Newberry SJ, Maher AR, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. JAMA. 2012;307:1959-1969.

2. Procter & Gamble. Align product information. Procter & Gamble Align Web site. Available at: http://www.aligngi.com/information-on-Align-probiotic-supplement. Accessed February 13, 2015.

3. Bayer HealthCare. Phillip’s Colon Health product information. Bayer HealthCare Phillip’s Colon Health Web site. Available at: http://phillipspro.com/en/home/product-information/index.php. Accessed February 13, 2015.

4. Nature’s Bounty. Nature’s Bounty Acidophilus Probiotic product label. Nature’s Bounty Web site. Available at: http://images.vitaminimages.com/cdn/sd/pdf/L002610-NB.PDF. Accessed February 13, 2015.

5.  Dannon. Activia. Dannon Activia Web site. Available at: http://activia.us.com/probiotic-yogurt/activia. Accessed February 13, 2015.

6. Lifeway. Lifeway Kefir frequently asked questions. Lifeway Kefir Web site. Available at: http://lifewaykefir.com/faq/. Accessed February 13, 2015.

7. Allen SJ, Martinez EG, Gregorio GV, et al. Probiotics for treating acute infectious diarrhoea. Cochrane Database Syst Rev. 2010;(11):CD003048.

8. McFarland LV. Meta-analysis of probiotics for the prevention of traveler’s diarrhea. Travel Med Infect Dis. 2007;5:97-105.

9. Hamad A, Fragkos KC, Forbes A. A systemic review and meta-analysis of probiotics for the management of radiation induced bowel disease. Clin Nutr. 2013;32:353-360.

10. Videlock EJ, Cremonini F. Meta-analysis: probiotics in antibiotic-associated diarrhoea. Aliment Pharmacol Ther. 2012;35:1355-1369.

11. Pillai A, Nelson RL. Probiotics for treatment of Clostridium difficile-associated colitis in adults. Cochrane Database Syst Rev. 2008;(1):CD004611.

12. Johnston BC, Ma SY, Goldenberg JZ, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and meta-analysis. Ann Intern Med. 2012;157:878-888.

13. Szajewska H, Horvath A, Piwowarczyk A. Meta-analysis: the effects of Saccharomyces boulardii supplementation on Helicobacter pylori eradication rates and side effects during treatment. Aliment Pharmacol Ther. 2010;32:1069-1079.

14. Sachdeva A, Nagpal J. Effect of fermented milk-based probiotic preparations on Helicobacter pylori eradication: a systematic review and meta-analysis of randomized-controlled trials. Eur J Gastroenterol Hepatol. 2009;21:45-53.

15. Wang ZH, Gao QY, Fang JY. Meta-analysis of the efficacy and safety of Lactobacillus-containing and Bifidobacterium-containing probiotic compound preparation in Helicobacter pylori eradication therapy. J Clin Gastroenterol. 2013;47:25-32.

16. Butterworth AD, Thomas AG, Akobeng AK. Probiotics for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2008;16:CD006634.

17. Rolfe VE, Fortun PJ, Hawkey CJ, et al. Probiotics for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev. 2006;(4):CD004826.

18. Mallon P, McKay D, Kirk SJ, et al. Probiotics for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2007;(4):CD005573.

19. Naidoo K, Gordon M, Fagbemi AO, et al. Probiotics for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2011;(12):CD007443.

20. Guglielmetti S, Mora D, Gschwender M, et al. Randomised clinical trial: Bifidobacterium bifidum MIMBb75 significantly alleviates irritable bowel syndrome and improves quality of life–– a double-blind, placebo-controlled study. Aliment Pharmacol Ther. 2011;33:1123-1132.

21. Moayyedi P, Ford AC, Talley NJ, et al. The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review. Gut. 2010;59:325-332.

22. Allen SJ, Wareham K, Wang D, et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2013;382:1249-1257.

23. Roberts LM, McCahon D, Holder R, et al. A randomised controlled trial of a probiotic ‘functional food’ in the management of irritable bowel syndrome. BMC Gastroenterol. 2013;13:45.

Probiotics—live micoorganisms that are consumed as supplements or food for purported health benefits—are a popular over-the-counter remedy for various gastrointestinal (GI) ailments and other conditions, but the evidence supporting their use is mixed. Probiotics interact with the normal flora of the human body. They are believed to act by multiple mechanisms to deliver beneficial effects, including providing a protective barrier, altering intestinal pH to favor the growth of nonpathogenic bacteria, enhancing the host’s immunologic response, producing antimicrobial substances, and directly competing with pathogenic bacteria for receptors in the GI tract.¹ (See “The normal human intestinal flora.”)

In the United States, Lactobacillus and Bifidobacterium are the probiotic genera that are most commonly used. (For a list of the specific probiotic species found in 5 popular products, see TABLE 1.^2-6) The review that follows examines the evidence for using probiotics for select GI ailments, including several types of diarrheal illnesses, inflammatory bowel disease (Crohn’s disease and ulcerative colitis), and irritable bowel syndrome (IBS). These findings are summarized in TABLE 2.^1,7-21

Probiotics may help with some types of diarrhea

Acute infectious diarrhea. Viruses, bacteria, and parasites cause acute infectious diarrhea, and probiotics are thought to act against these pathogens by competing for available nutrients and pattern recognition receptors in the GI endothelium, acidifying the local environment, and increasing immune responses within the GI tract. In a meta-analysis of 63 studies (N=8014) that used multiple strains and dosages of probiotics, investigators found probiotics shortened the duration of acute infectious diarrhea by approximately 24 hours (95% confidence interval [CI], 15.9-33.6 hours).⁷ Probiotics also reduced both the risk of diarrhea lasting longer than 4 days (relative risk [RR]=0.41; 95% CI, 0.32-0.53) and stool frequency on Day 2 of illness (mean difference of 0.80 stools; 95% CI, 0.45-1.14).

Traveler’s diarrhea. The incidence of traveler’s diarrhea is >50% when traveling to high-risk areas such as the Middle East, North Africa, Latin America, and Southeast Asia, and 5% to 10% when traveling to areas such as North America, Northern Europe, the United Kingdom, Australia, and New Zealand.⁸ Traveler’s diarrhea may be caused by ingesting food and liquids contaminated with fecal material. Symptoms include diarrhea, cramps, and nausea that if untreated typically last from 2 to 6 days but can last for as long as a month.⁸

In a meta-analysis of 12 studies (N=5171) that evaluated various probiotic strains, researchers found probiotics effectively prevented traveler’s diarrhea in US and European travelers who visited a variety of vacation spots (pooled RR=0.85; 95% CI, 0.79-0.91).⁸ No serious adverse events were reported.

Radiation-induced diarrhea. Radiation treatments to the abdomen and pelvis can damage the lower GI tract and cause diarrhea. The pooled results from a meta-analysis that included 6 studies (N=1449) significantly favored the use of probiotics over placebo for decreasing the incidence of radiation-induced diarrhea (odds ratio [OR]=0.44; 95% CI, 0.21-0.92).⁹ Probiotics use also was associated with decreased loperamide use (OR=0.29; 95% CI, 0.01-6.80) and decreased incidence of watery stools (OR=0.36; 95% CI, 0.05-2.81), but these outcomes did not reach statistical significance.

Antibiotic-associated diarrhea. Antibiotic use has long been associated with the development of diarrheal illness, sometimes due to the acceleration of GI motility (eg, erythromycin) or by causing osmotic diarrhea by decreasing GI bacteria that assist in carbohydrate breakdown.¹¹ A meta-analysis that evaluated 63 randomized controlled trials (RCTs) (N=11,811) showed that probiotics are effective for treating and preventing antibiotic-associated diarrhea (AAD).¹ There was a statistically significant reduction in AAD among patients who received probiotics (RR=0.58; 95% CI, 0.50-0.68; number needed to treat [NNT]=13). Most of the studies in this meta-analysis used a Lactobacillus probiotic alone or in combination with another probiotic. Researchers did not analyze whether the efficacy varied by patient population, probiotic used, causative antibiotic, or duration of treatment.¹

Another meta-analysis of 34 studies (N=4138) also found probiotic therapy can prevent AAD.¹⁰ The pooled RR for AAD was 0.53 (95% CI, 0.44-0.63) for patients treated with probiotics compared to placebo, with an NNT of 8 (95% CI, 7-11). The effects remained significant when results were grouped by probiotic species, patient age, and duration of antibiotic treatment. Among a subgroup of patients in this meta-analysis who were being treated for Helicobacter pylori, the pooled RR of AAD was 0.37 (95% CI, 0.20-0.69) and the NNT was 5 (95% CI, 4-10).¹⁰ However, the 2013 PLACIDE trial (N=17,420) found no significant decrease in AAD rates in hospitalized patients over age 65 years being treated with antibiotics who received probiotics (RR=1.04; 95% CI, 0.84-1.28).²²

Clostridium difficile-associated diarrhea. As we know, antibiotics can disrupt the normal GI flora and permit overgrow of Clostridium difficile, which can result in C. difficile-associated diarrhea (CDAD).¹² This can occur with oral, parenteral, and even topical antibiotics.¹¹ Researchers have investigated whether probiotics can prevent this opportunistic C. difficile overgrowth.

A 2012 meta-analysis of 20 trials (N=38,180) found probiotic prophylaxis prevented CDAD in both inpatients and outpatients while not increasing the incidence of significant adverse effects.¹² Probiotics decreased the incidence of CDAD by 66% (pooled RR=0.34, 95% CI, 0.24-0.49).¹² Adverse events occurred in 9.3% of patients taking probiotics, compared with 12.6% of controls (RR=0.82, 95% CI, 0.65-1.05).¹²

Conversely, a 2008 review of 4 studies (N=336) concluded there is insufficient evidence for using probiotics to treat CDAD, either as monotherapy or adjunct therapy.¹¹ One trial in this meta-analysis (N=124) found patients who received the probiotic Saccharomyces boulardii in addition to antibiotic therapy were significantly less likely to experience CDAD recurrence than those who received placebo (RR=0.59; 95% CI, 0.35-0.98).¹¹ However, this benefit was not found in the other trials in this meta-analysis.¹¹

The PLACIDE trial found probiotics did not prevent CDAD in hospitalized patients over age 65 years; 0.8% of patients who received probiotics developed CDAD, compared to 1.2% in the placebo group (RR=0.71, 95% CI, 0.34-1.47).²²

Helicobacter pylori infection. The triple therapy regimen of a proton pump inhibitor plus the antibiotics clarithromycin and amoxicillin is the recommended treatment for H. pylori infection.¹³ Problems with this treatment include adverse effects such as diarrhea and decreased eradication rates, in part due to antibiotic resistance. Certain Lactobacillus species have been shown to inhibit or kill H. pylori in vitro,¹³ and evidence from several meta-analyses suggests probiotics should be an adjunct therapy when treating H. pylori.

In a meta-analysis of 10 RCTs (N=963), fermented milk-based probiotics improved H. pylori eradication rates by 5% to 15%.¹⁴ In another meta-analysis that evaluated 5 RCTs (N=1307), S. boulardii significantly increased the H. pylori eradication rate when used as an adjunct to triple therapy (RR=1.13; 95% CI, 1.05-1.21) and reduced the rate of treatment-related adverse effects (RR=0.46; 95% CI, 0.3-0.7).¹³ In a third meta-analysis of 10 trials (N=1469), Lactobacillus supplementation increased H. pylori eradication rates (OR=2.1; 95% CI, 1.4-3.1) while decreasing the overall incidence of adverse effects (OR=0.3; 0.1-0.8).¹⁵

For inflammatory bowel disease, probiotics are unlikely to help

Current therapies for Crohn’s disease and ulcerative colitis, such as corticosteroids and other immunosuppressive agents, are effective but have significant adverse events.¹⁸ Researchers explored whether probiotics might help treat these diseases by improving immune response, the balance of microbes in the GI tract, and the intestinal barrier.¹⁸

Crohn’s disease. In a meta-analysis that was able to identify only one small RCT (N=11), 80% of patients receiving probiotic treatment went into remission, compared to 83% in the placebo group (OR=0.80; 95% CI, 0.04–17.20).¹⁶ Researchers concluded there was insufficient evidence for the use of probiotics for inducing remission in Crohn’s disease.

Another meta-analysis of 7 small studies (N=160) found no significant evidence supporting probiotic use for maintaining remission in Crohn’s disease compared with aminosalicylates or azathioprine.¹⁷ One small study in this review found there was a benefit to combining S. boulardii with a reduced level of standard maintenance therapy when compared to standard therapy alone, but this difference was not statistically significant.¹⁷

Ulcerative colitis. A systematic review of 4 RCTs (N=244) that compared conventional treatment alone to conventional treatment plus probiotics for remission or clinical improvement in patients with active ulcerative colitis found no significant differences between groups.¹⁸ Another meta-analysis of 4 studies (N=587) found that compared to placebo or treatment with mesalazine, probiotics had no benefit for maintaining remission in ulcerative colitis.¹⁹ The rate of relapse was 40.1% in the probiotics group compared to 34.1% in the mesalazine group. The number of adverse effects was similar in both groups.

Most evidence suggests probiotics are useful for IBS

In RCTs, probiotic supplements—but not yogurt containing probiotics—reduced IBS symptoms. Research suggests that imbalances in GI flora, along with subsequent dysfunction in intestinal barriers and translocation of intestinal flora, may play a role in symptoms associated with IBS, such as abdominal pain, bloating, and diarrhea/constipation.²⁰ There are few effective therapeutic options for patients suffering with IBS.

In a systematic review of 19 RCTs (N=1650), probiotics were significantly more effective than placebo for patients with IBS, with an NNT of 4 (95% CI, 3-12.5).²¹ This review did not evaluate the difference between various probiotic species and strains.

In an RCT (N=122), the probiotic strain Bifidobacterium bifidum MIMBb75 was found to be safe and beneficial for treating IBS symptoms and improving patients’ quality of life.²⁰ On a 7-point scale of global assessment of IBS symptoms, the score was reduced by 0.88 points (95% CI, 0.69-1.07) in the group that received B. bifidum MIMBb75 and 0.16 points (95% CI, -0.32-0.00) in the placebo group (P<0.0001). Almost half (47%) of the patients who received B. bifidum MIMBb75 reported adequate relief, compared to 11% in the placebo group (P<.0001).

An RCT (N=179) that compared yogurt that contained probiotics to non-probiotic yogurt found the probiotic yogurt had no benefits for treating IBS symptoms.²³ After 4 weeks, 57% of patients who ate the probiotic yogurt reported adequate relief, compared to 53% of those who ate non-probiotic yogurt (P=0.71). After 8 weeks, those numbers were 47% and 68%, respectively.²³

CORRESPONDENCE
Erik R. Clauson, DO, Nellis Family Medicine Residency, 99 MDOS/SGOF, 4700 Las Vegas Boulevard North, Nellis Air Force Base, NV 89191; [email protected] 

REFERENCES

1. Hempel S, Newberry SJ, Maher AR, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. JAMA. 2012;307:1959-1969.

2. Procter & Gamble. Align product information. Procter & Gamble Align Web site. Available at: http://www.aligngi.com/information-on-Align-probiotic-supplement. Accessed February 13, 2015.

3. Bayer HealthCare. Phillip’s Colon Health product information. Bayer HealthCare Phillip’s Colon Health Web site. Available at: http://phillipspro.com/en/home/product-information/index.php. Accessed February 13, 2015.

4. Nature’s Bounty. Nature’s Bounty Acidophilus Probiotic product label. Nature’s Bounty Web site. Available at: http://images.vitaminimages.com/cdn/sd/pdf/L002610-NB.PDF. Accessed February 13, 2015.

5.  Dannon. Activia. Dannon Activia Web site. Available at: http://activia.us.com/probiotic-yogurt/activia. Accessed February 13, 2015.

6. Lifeway. Lifeway Kefir frequently asked questions. Lifeway Kefir Web site. Available at: http://lifewaykefir.com/faq/. Accessed February 13, 2015.

7. Allen SJ, Martinez EG, Gregorio GV, et al. Probiotics for treating acute infectious diarrhoea. Cochrane Database Syst Rev. 2010;(11):CD003048.

8. McFarland LV. Meta-analysis of probiotics for the prevention of traveler’s diarrhea. Travel Med Infect Dis. 2007;5:97-105.

9. Hamad A, Fragkos KC, Forbes A. A systemic review and meta-analysis of probiotics for the management of radiation induced bowel disease. Clin Nutr. 2013;32:353-360.

10. Videlock EJ, Cremonini F. Meta-analysis: probiotics in antibiotic-associated diarrhoea. Aliment Pharmacol Ther. 2012;35:1355-1369.

11. Pillai A, Nelson RL. Probiotics for treatment of Clostridium difficile-associated colitis in adults. Cochrane Database Syst Rev. 2008;(1):CD004611.

12. Johnston BC, Ma SY, Goldenberg JZ, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and meta-analysis. Ann Intern Med. 2012;157:878-888.

13. Szajewska H, Horvath A, Piwowarczyk A. Meta-analysis: the effects of Saccharomyces boulardii supplementation on Helicobacter pylori eradication rates and side effects during treatment. Aliment Pharmacol Ther. 2010;32:1069-1079.

14. Sachdeva A, Nagpal J. Effect of fermented milk-based probiotic preparations on Helicobacter pylori eradication: a systematic review and meta-analysis of randomized-controlled trials. Eur J Gastroenterol Hepatol. 2009;21:45-53.

15. Wang ZH, Gao QY, Fang JY. Meta-analysis of the efficacy and safety of Lactobacillus-containing and Bifidobacterium-containing probiotic compound preparation in Helicobacter pylori eradication therapy. J Clin Gastroenterol. 2013;47:25-32.

16. Butterworth AD, Thomas AG, Akobeng AK. Probiotics for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2008;16:CD006634.

17. Rolfe VE, Fortun PJ, Hawkey CJ, et al. Probiotics for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev. 2006;(4):CD004826.

18. Mallon P, McKay D, Kirk SJ, et al. Probiotics for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2007;(4):CD005573.

19. Naidoo K, Gordon M, Fagbemi AO, et al. Probiotics for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2011;(12):CD007443.

20. Guglielmetti S, Mora D, Gschwender M, et al. Randomised clinical trial: Bifidobacterium bifidum MIMBb75 significantly alleviates irritable bowel syndrome and improves quality of life–– a double-blind, placebo-controlled study. Aliment Pharmacol Ther. 2011;33:1123-1132.

21. Moayyedi P, Ford AC, Talley NJ, et al. The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review. Gut. 2010;59:325-332.

22. Allen SJ, Wareham K, Wang D, et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2013;382:1249-1257.

23. Roberts LM, McCahon D, Holder R, et al. A randomised controlled trial of a probiotic ‘functional food’ in the management of irritable bowel syndrome. BMC Gastroenterol. 2013;13:45.

Approximately 5.5 million patients undergo orthopedic surgery in the United States each year, and more than 1 million of the procedures are total knee arthroplasty (TKA) or total hip arthroplasty.¹ From its 2010 level, demand for joint arthroplasty is expected to double by 2020 and quadruple by 2030.²

About half the patients who have major joint arthroplasty experience severe postsurgical pain.³ Because postsurgical pain may persist for days or weeks, and inadequate treatment is associated with negative outcomes, achieving effective postsurgical analgesia is an important consideration.^4-7 Complications of inadequate postsurgical pain management include thromboembolic or pulmonary complications, development of chronic pain, and decrements in health-related quality of life.^4,8

In patients who have orthopedic surgery, the inability to adequately control postsurgical pain has been associated with increased hospital length of stay (LOS), delayed time to ambulation, and reduced capacity for exercise.^9-12 A recent study involving 4709 patients who had hip or knee arthroplasty found that postsurgical pain relief was the second most highly correlated factor with respect to overall patient satisfaction (how well surgery met patient expectations was the most highly correlated factor),¹³ suggesting that postsurgical analgesia should be a focus of surgical practice.

A prolonged-release liposomal formulation of the local anesthetic bupivacaine is now available. Bupivacaine liposome injectable suspension (Exparel; Pacira Pharmaceuticals, Inc., Parsippany, New Jersey) is indicated for administration into the surgical site to produce postsurgical analgesia.¹⁴ In this article, we review evidence from clinical studies regarding the potential contribution of liposome bupivacaine to improving postsurgical pain management when used as part of a multimodal analgesic regimen in patients undergoing orthopedic surgery.

Postsurgical Pain Management in Orthopedic Surgery

Frequently Used Modalities

Analgesic modalities commonly used for perioperative pain management include central (eg, epidural),^4,10,15,16 central regional (eg, neuraxial),⁴ peripheral regional (eg, peripheral nerve blocks, local/regional surgical site infiltration, intra-articular administration),^{4,10,15,17-25} and intravenous (IV) patient-controlled analgesia.^4,10,25 These pharmacologic interventions may be augmented by nonpharmacologic modalities (eg, transcutaneous electrical nerve stimulation).²⁶

Pharmacologic treatment options for perioperative pain management include opioids, local anesthetics, clonidine, ketamine, nonsteroidal anti-inflammatory drugs, acetaminophen, and calcium-channel blockers.^4,26-28 In TKA, “drug cocktails” (eg, combinations of ropivacaine, ketorolac, epinephrine, and clonidine) for regional or intra-articular injection can also provide effective immediate postsurgical analgesia.²⁵ Although opioids are the most commonly used analgesics for management of orthopedic perioperative pain,²⁵ their use is often associated with adverse effects (AEs), including constipation or ileus, nausea, sedation, dizziness, pruritus, urinary retention, and respiratory depression.⁶

Multimodal Analgesic Regimens for Postsurgical Pain Management

Current American Society of Anesthesiologists guidelines endorse use of multimodal analgesia, whenever possible, to provide effective management of acute perioperative pain.⁴ Multimodal analgesia involves applying 2 or more agents with different mechanisms of action to achieve a synergistic effect, which allows each agent to be reduced in dose^4,28 and thereby may limit the risk and severity of dose-related AEs.^4,25,28

Multimodal analgesia aims to reduce the risk for opioid-related AEs (ORAEs) and the impact of opioids on postsurgical milestones (eg, ambulation, discharge) and may reduce opioid consumption, with attendant reductions in ORAE risk.^29,30 Health economics studies have shown that postsurgical ORAEs are associated with increased hospital costs and LOS.⁶ In a study using a national hospital database, development of an ORAE (vs no ORAE) in postsurgical patients was associated with mean increases of about $4700 in hospital costs and 3.3 days in LOS.⁷ Reducing postsurgical opioid use may also help reduce the risk for opioid abuse, addiction, and diversion.^31-33

One approach to reducing opioid use involves continuous or intermittent administration of local anesthetics by elastomeric pumps to extend duration of postsurgical analgesia.^34-36 However, use of elastomeric pumps has been associated with risk for AEs, including tissue necrosis, sloughing, wound infection, and chondrolysis.^37-40 In addition, AEs related to “dose dumping” (accidental delivery of excessive doses) have been reported.^40-44 Key issues that may negatively affect rehabilitation after orthopedic surgery include consistency and accuracy of analgesic delivery and the potential for motor block–induced muscle weakness, which may lead to falls and constrain ambulation.^45-47

Liposome Bupivacaine

Description

Drug Delivery Technology. Liposome bupivacaine incorporates DepoFoam drug delivery technology (Pacira Pharmaceuticals, Inc.) to facilitate prolonged release of bupivacaine. This technology is based on creation of multivesicular liposome particles (diameter, 10-30 µm) with multiple aqueous chambers.^30,48 After administration into the surgical site, bupivacaine diffuses from chambers in the liposomal particles over time, providing analgesia and reduced opioid requirements for up to 72 hours.^29,30

Indication, Mechanism of Action, Pharmacokinetics, and Dose/Administration. Liposome bupivacaine is indicated for single-dose administration into the surgical site to produce postsurgical analgesia in patients at least 18 years old.¹⁴ Like other local anesthetics, liposome bupivacaine is thought to exert its pharmacologic effects by interacting with voltage-gated Na⁺ channels on neural membranes to raise the threshold for electrical excitability, to slow nerve impulse propagation, and to reduce the rate of rise of the action potential.^14,49

Liposome bupivacaine has dose-proportional pharmacokinetics.⁵⁰ Presence of a small amount of extra-liposomal bupivacaine in the formulation leads to a bimodal pharmacokinetic profile, with an initial peak serum concentration about 1 hour after administration, followed by a second peak within 12 to 36 hours (Figure).⁵⁰

Maximum amount of liposome bupivacaine approved for single administration is 266 mg (packaged as 20 mL of a 1.3% solution). However, product labeling includes safety data associated with doses of 532 mg or less.¹⁴ The appropriate volume to be used should be based on the amount required to cover the surgical area. Liposome bupivacaine may be expanded with preservative-free normal (0.9%) sterile saline to a total volume of 300 mL: 20 mL liposome bupivacaine plus 280 mL or less diluent, with final concentration of 0.89 mg/mL (1:14 by volume).¹⁴

A 25-gauge or larger bore needle should be used to slowly inject liposome bupivacaine into soft tissues of the surgical site, with frequent aspiration to check for blood to minimize risk for intravascular injection.¹⁴ Total volume used and fraction injected in specific regions of the surgical site depend on the procedure. For example, a TKA study used 266 mg diluted to a total volume of 60 mL, with 8 mL infiltrated to the area around the medial capsule, 8 mL around the lateral capsule, 12 mL around the posterior capsule, 8 mL around the peripatellar area, 12 mL into the capsulotomy incision, and 12 mL into the subcutaneous tissue on each side of the incision.⁵¹

Efficacy

Multiple Surgical Settings. The efficacy of liposome bupivacaine, either alone or as a component of a multimodal analgesic regimen, has been evaluated in a series of 10 phase 2 and 3 studies (8 active-controlled, 2 placebo-controlled) involving 823 patients undergoing TKA, bunionectomy, hemorrhoidectomy, inguinal hernia repair, or mammoplasty.⁵² Patients received a single liposome bupivacaine dose ranging from 66 to 532 mg.⁵²

Combined analyses of efficacy data from these studies found that liposome bupivacaine–based multimodal analgesic regimens produced postsurgical analgesia for up to 72 hours, increased time to first use of opioid rescue medication after surgery, and reduced total amount of postsurgical opioid consumption versus placebo.⁵²

Compared with standard of care, liposome bupivacaine has been shown to provide effective analgesia in open-label studies in patients undergoing open colectomy,⁵³ laparoscopic colectomy,⁵⁴ and ileostomy reversal,^55,56 as reflected in assessments of postsurgical opioid consumption, LOS, and hospital costs. It has also been studied when administered by infiltration into the transversus abdominis plane (TAP) in patients having laparoscopic prostatectomy and open abdominal hernia repair.^57,58

Orthopedic Surgery. In a phase 2 randomized, double-blind, dose-ranging study, TKA patients (N = 138) received bupivacaine HCl 150 mg or liposome bupivacaine 133, 266, 399, or 532 mg administered by local infiltration into the capsulotomy incision and on either side of the incision before wound closure.⁵¹ Postsurgical rescue analgesia was available to all patients. Cumulative pain intensity scores with activity (primary efficacy measure) were not statistically different between liposome bupivacaine groups and the bupivacaine HCl group through postoperative day 4. Mean scores in the liposome bupivacaine 266-, 399-, and 532-mg groups were numerically lower than for those treated with bupivacaine HCl on postoperative days 2 to 5, with all doses of liposome bupivacaine having a statistically significant lower pain score at rest on day 5. There were no statistically significant differences across treatment groups with respect to total amount of postsurgical opioids used.

In a phase 3 randomized, double-blind study of TKA patients (N = 245), liposome bupivacaine 532 mg administered into the surgical site was compared with bupivacaine HCl 200 mg for postsurgical analgesia.⁵² Rescue analgesia was available to all patients. No statistically significant between-group differences were found with respect to postsurgical cumulative pain scores through 72 hours (primary efficacy endpoint).

In a single-center retrospective TKA study, postsurgical outcomes in a patient cohort that received intraoperative periarticular infiltration with liposome bupivacaine 266 mg (n = 65) were compared with a cohort that received infiltration with a combination of ropivacaine 400 mg, morphine 5 mg, and epinephrine 0.4 mg (n = 85).⁵⁹ Patient-reported postsurgical pain scores were similar in the 2 treatment groups during the first 24 hours after surgery and at discharge. Mean (SD) pain scores during hospitalization after the first 24 hours until discharge were significantly (P = .04) higher in the liposome bupivacaine group, 4.9 (1.4), than in the periarticular group, 4.4 (1.6). There was no significant difference between the 2 treatment groups in postsurgical opioid use. The study demonstrated no advantage to using liposome bupivacaine injections with respect to pain relief, but it was a retrospective review in which pain scores were obtained from electronic medical records. It is essential that liposome bupivacaine be compared with intra-articular injections in well-designed randomized trials.

Another single-center, matched-cohort TKA study (N = 200) compared a liposome bupivacaine regimen with femoral nerve block.⁶⁰ Compared with patients who received femoral nerve block, patients who received liposome bupivacaine reported lower pain intensity scores after surgery and had shorter LOS, reduced costs, and improved knee flexion at follow-up.⁶⁰

Results from 2 other studies were presented at the 2014 meeting of the American Academy of Orthopaedic Surgeons (AAOS). One was a single-center, matched-cohort TKA study (N = 72) comparing infiltration of a single dose of liposome bupivacaine into the surgical site with continuous femoral nerve block.⁶¹ The 2 treatment groups had similar mean postsurgical pain intensity scores on a 0-to-10 visual analog scale, 1.8 for liposome bupivacaine and 2.3 for continuous nerve block (P = NS), but total amount of postsurgical opioids (hydrocodone-equivalent milligrams) was significantly (P < .0001) less in the liposome bupivacaine group (82 vs 177 mg).

The other study presented at the AAOS meeting was a larger, prospective case–control study comparing outcomes between 1000 patients who had total joint arthroplasty (TJA) with liposome bupivacaine and 1000 control patients who had TJA without liposome bupivacaine.⁶² For the control and liposome bupivacaine cohorts, respectively, mean postsurgical pain intensity scores were 2.41 and 1.98 (P < .0001), mean LOS was 2.83 days and 2.66 days (P < .02), and incidence of falls was 1.0% and 0.2% (P = .02). Average per-patient costs were $1246 lower in the liposome bupivacaine cohort.

A pivotal phase 3 placebo-controlled study compared liposome bupivacaine 106 mg with placebo in patients undergoing bunionectomy (N = 193).⁵ Rescue medication was available to all patients. Cumulative pain scores were significantly (P = .0005) lower in the liposome bupivacaine group (125) than in the placebo group (146) through 24 hours after surgery (primary efficacy measure) and significantly (P = .0229) lower (197 vs 220) through 36 hours. Median time to first use of rescue opioids was delayed in favor of the liposome bupivacaine group (7.2 vs 4.3 hours; P < .0001). Mean total number of opioid tablets used within 24 hours after surgery was also significantly lower (3.8 vs 4.7; P = .008), and a larger percentage of patients in the liposome bupivacaine group avoided opioid use altogether through 24 hours (7% vs 1%; P = .04).

Efficacy data for liposome bupivacaine appear promising for relief of pain after joint arthroplasty and other orthopedic procedures but have their limitations. First, no randomized trials have compared liposome bupivacaine with locally injected pain medications (intra-articular injections in TKA or hip arthroplasty). As these injections are quite common now, such analyses are essential. Second, cost-effectiveness studies are needed for orthopedic procedures. Third, most of the published studies were sponsored by the manufacturer of liposome bupivacaine—a situation that raises questions about potential bias. Non-industry-sponsored randomized trials assessing efficacy, safety, and cost-effectiveness are needed.

Safety

Local anesthetics, including liposome bupivacaine, have the potential for central nervous system (CNS) or cardiac toxicity resulting from excessive systemic absorption or inadvertent IV administration.⁶³ However, reported serious CNS or cardiac-related AEs are rare.^63,64

AE Profile. Safety data from 10 phase 2 and 3 studies involving 823 patients who received liposome bupivacaine were evaluated.⁶⁵ Of these patients, 545 received a dose of 266 mg or less (maximum dose approved by the US Food and Drug Administration [FDA]). Liposome bupivacaine was generally well tolerated. Reported AE incidence was 62% (liposome bupivacaine), 75% (bupivacaine HCl), and 43% (placebo). More than 90% of reported AEs were mild or moderate. The most frequently reported AEs were nausea, constipation, and vomiting (liposome bupivacaine, bupivacaine HCl) and nausea, dizziness, and vomiting (placebo).

Serious AEs were reported in 22 (2.7%) of the 823 patients in the liposome bupivacaine group, 24 (5.4%) of the 446 in the bupivacaine HCl group, and 2 (1.1%) of the 190 in the placebo group.⁶⁵ None of the serious AEs in the liposome bupivacaine and placebo groups were considered treatment-related. Six patients in the bupivacaine HCl group had treatment-related serious AEs (hypoglycemia, arthrofibrosis, hemarthrosis, joint swelling, scar, knee arthroplasty).

Cardiac Safety. Possible cardiac effects associated with liposome bupivacaine were evaluated with data from studies conducted during the clinical development program.⁶⁶ One hundred thirty-eight patients participated in the phase 2 safety and efficacy study in TKA. In these patients, a consistent change in mean heart rate (range, +12.2 to +16.5 beats per minute) was found across all liposome bupivacaine doses and with bupivacaine HCl. No clinically relevant changes from baseline in mean electrocardiographic parameters, including QTcF interval (QT interval adjusted using Fridericia’s correction formula), were found. In another analysis,⁶⁷ liposome bupivacaine administered in a single subcutaneous dose (266, 399, 532, or 665 mg) to healthy volunteers did not prolong (vs placebo) QTc interval.

Wound Healing. The potential effects of liposome bupivacaine on wound healing were evaluated with results from 10 phase 2 and 3 studies.⁶⁸ The assessments, which varied across studies, included clinicians’ overall satisfaction with patient wound healing, wound status assessment (categories included erythema, drainage, edema, and induration), and wound scarring (categories included pigmentation, height, pliability, and vascularity). Clinician-assessed scores reflected high satisfaction with wound healing overall. There were few statistically significant differences in wound status assessments between liposome bupivacaine and the comparators and no statistically significant differences in scarring between liposome bupivacaine and bupivacaine HCl.

The potential of liposome bupivacaine to have adverse intra-articular effects was assessed with drainage samples from patients (n = 23) who had TKA and received liposome bupivacaine (133, 266, 399, or 532 mg) or bupivacaine HCl (150 mg) by wound infiltration near the intra-articular space.^51,65 Only small amounts of bupivacaine were present in drainage fluid collected for 12 hours after liposome bupivacaine administration, comparable to bupivacaine HCl administration.⁶⁵ Currently, the product is not approved for intra-articular use.

Compatibility With Diluents, Other Medications, and Implant Materials

Liposome bupivacaine may be expanded up to a ratio of 1:14 by volume (to a final total volume of 300 mL or a concentration of 0.89 mg/mL) using preservative-free normal (0.9%) sterile saline for injection.¹⁴ It has also been shown in vitro to be compatible with lactated Ringer solution as a diluent.⁶⁹

Liposome bupivacaine should not be admixed with other medications before administration.¹⁴ No formal drug–drug interaction studies have been conducted with liposome bupivacaine, but it has been shown in vitro to be compatible with epinephrine solutions, with certain anti-infective medications (eg, bacitracin, gentamicin, cefazolin, cefuroxime), with certain analgesics (eg, ketorolac, morphine), with an antihypertensive medication (clonidine), with an antihemorrhagic medication (tranexamic acid), and with certain corticosteroids (eg, methylprednisolone, triamcinolone acetonide). These medications may be coadministered in the same location as liposome bupivacaine.⁶⁹

Topical antiseptics (eg, povidone iodine) may be used in surgical procedures involving liposome bupivacaine as long as they are not directly mixed with liposome bupivacaine and are allowed to dry before it is administered. If a topical antiseptic is used for wound irrigation, the wound should be rinsed clear before liposome bupivacaine administration.^14,69

Liposome bupivacaine may be coadministered into the same surgical site immediately after bupivacaine HCl as long as the dose ratio of liposome bupivacaine to bupivacaine HCl is 2:1 or higher. Because of the prolonged-release pharmacokinetic profile of liposome bupivacaine and the potential for increased bupivacaine exposure, bupivacaine HCl should not be administered within 96 hours after administration of liposome bupivacaine.^14,69

In vitro coincubation studies of liposome bupivacaine and other local anesthetics, including ropivacaine, lidocaine, and mepivacaine, have found rapid release of free bupivacaine from the liposome matrix. Therefore, after giving any of these other local anesthetics, surgeons should wait at least 20 minutes before administering liposome bupivacaine into the same area.^14,69

In vitro studies have shown that liposome bupivacaine is compatible with a wide range of commonly used implant materials, including polypropylene, expanded polytetrafluoroethylene, stainless steel, titanium, and smooth- and textured-type silicone.⁶⁹

Investigational Use and Ongoing Studies

A phase 2 randomized, double-masked, dose-escalating/deescalating study was conducted to evaluate the efficacy, safety, and pharmacokinetics of liposome bupivacaine (155, 199, or 310 mg) in comparison with bupivacaine HCl 125 mg for ankle nerve block in patients undergoing bunionectomy (N = 58).⁷⁰ The study medication was injected into 3 sites to reach the posterior tibial, sural, deep peroneal, superficial peroneal, and saphenous nerves. Pharmacokinetic exposure was higher for liposome bupivacaine than for bupivacaine HCl, as reflected by a significantly greater area under the curve, lower C_max (maximum serum concentration), and longer mean half-life. Mean pain intensity scores were lower in the bupivacaine HCl group than in each liposome bupivacaine group the first 12 hours after surgery. However, the liposome bupivacaine 310-mg group had similar or lower scores than the bupivacaine HCl group from 12 to 96 hours after surgery. The most common AEs in the liposome bupivacaine group were gastrointestinal and not treatment-related.⁷⁰

The efficacy and safety of liposome bupivacaine, administered as a femoral nerve block for postsurgical analgesia, were assessed in a phase 2/3 manufacturer-sponsored, placebo-controlled, multicenter, randomized, double-blind 2-part study (NCT01683071)⁷¹ in 280 TKA patients.^71,72 Part 2 of the study, comparing liposome bupivacaine 266 mg (n = 116) and placebo (n = 116), met its primary endpoint, demonstrating statistical significance in favor of liposome bupivacaine for cumulative pain scores over 72 hours (P < .0001), with decreased opioid use (P < .05) and a safety profile similar to that of placebo.⁷²

Other ongoing investigator-sponsored studies in orthopedic populations include comparisons of liposome bupivacaine and bupivacaine HCl for ultrasound-guided periarticular hip infiltration in hip arthroplasty (NTC01917191),⁷³ as femoral nerve block in TKA (NCT01977339),⁷⁴ and as interscalene brachial plexus block in arthroscopic shoulder surgery (NCT01977352).⁷⁵ The primary efficacy outcome measure in these studies was postsurgical opioid use.^73-75

Health Economics

A series of phase 4 health economics studies was conducted for gastrointestinal surgeries, including open colectomy, laparoscopic colectomy, and ileostomy reversal.^53-56,76 These studies, of similar design, showed that a liposome bupivacaine–based multimodal analgesic regimen was associated with reduced opioid use, shorter hospital LOS, and lower hospitalization costs in comparison with a traditional opioid-based regimen.^53-56 Although pooled analysis of these studies showed a cost savings of more than $2000 per patient and an LOS decrease of 1.4 days,⁷⁶ all were conducted in the gastrointestinal surgery setting. Studies are needed to fully assess the economic benefits associated with liposome bupivacaine in the orthopedic surgery setting.

Conclusion

Liposome bupivacaine represents a potentially important contributor to multimodal analgesic regimens used to manage postsurgical pain. Liposome bupivacaine has demonstrated efficacy in providing prolonged postsurgical analgesia and reducing postsurgical opioid use in most surgical settings studied. Additional data from health economics studies in gastrointestinal surgery suggest liposome bupivacaine–based multimodal analgesic regimens may also contribute to reductions in hospital LOS and hospitalization costs. Non-industry-sponsored trials are needed to answer these crucial questions in orthopedic surgery settings. Nevertheless, data on the safety and efficacy of liposome bupivacaine for postsurgical analgesia continue to accumulate, and liposome bupivacaine appears to be a feasible therapeutic option for managing postsurgical pain in orthopedic surgery.

Approximately 5.5 million patients undergo orthopedic surgery in the United States each year, and more than 1 million of the procedures are total knee arthroplasty (TKA) or total hip arthroplasty.¹ From its 2010 level, demand for joint arthroplasty is expected to double by 2020 and quadruple by 2030.²

About half the patients who have major joint arthroplasty experience severe postsurgical pain.³ Because postsurgical pain may persist for days or weeks, and inadequate treatment is associated with negative outcomes, achieving effective postsurgical analgesia is an important consideration.^4-7 Complications of inadequate postsurgical pain management include thromboembolic or pulmonary complications, development of chronic pain, and decrements in health-related quality of life.^4,8

In patients who have orthopedic surgery, the inability to adequately control postsurgical pain has been associated with increased hospital length of stay (LOS), delayed time to ambulation, and reduced capacity for exercise.^9-12 A recent study involving 4709 patients who had hip or knee arthroplasty found that postsurgical pain relief was the second most highly correlated factor with respect to overall patient satisfaction (how well surgery met patient expectations was the most highly correlated factor),¹³ suggesting that postsurgical analgesia should be a focus of surgical practice.

A prolonged-release liposomal formulation of the local anesthetic bupivacaine is now available. Bupivacaine liposome injectable suspension (Exparel; Pacira Pharmaceuticals, Inc., Parsippany, New Jersey) is indicated for administration into the surgical site to produce postsurgical analgesia.¹⁴ In this article, we review evidence from clinical studies regarding the potential contribution of liposome bupivacaine to improving postsurgical pain management when used as part of a multimodal analgesic regimen in patients undergoing orthopedic surgery.

Postsurgical Pain Management in Orthopedic Surgery

Frequently Used Modalities

Analgesic modalities commonly used for perioperative pain management include central (eg, epidural),^4,10,15,16 central regional (eg, neuraxial),⁴ peripheral regional (eg, peripheral nerve blocks, local/regional surgical site infiltration, intra-articular administration),^{4,10,15,17-25} and intravenous (IV) patient-controlled analgesia.^4,10,25 These pharmacologic interventions may be augmented by nonpharmacologic modalities (eg, transcutaneous electrical nerve stimulation).²⁶

Pharmacologic treatment options for perioperative pain management include opioids, local anesthetics, clonidine, ketamine, nonsteroidal anti-inflammatory drugs, acetaminophen, and calcium-channel blockers.^4,26-28 In TKA, “drug cocktails” (eg, combinations of ropivacaine, ketorolac, epinephrine, and clonidine) for regional or intra-articular injection can also provide effective immediate postsurgical analgesia.²⁵ Although opioids are the most commonly used analgesics for management of orthopedic perioperative pain,²⁵ their use is often associated with adverse effects (AEs), including constipation or ileus, nausea, sedation, dizziness, pruritus, urinary retention, and respiratory depression.⁶

Multimodal Analgesic Regimens for Postsurgical Pain Management

Current American Society of Anesthesiologists guidelines endorse use of multimodal analgesia, whenever possible, to provide effective management of acute perioperative pain.⁴ Multimodal analgesia involves applying 2 or more agents with different mechanisms of action to achieve a synergistic effect, which allows each agent to be reduced in dose^4,28 and thereby may limit the risk and severity of dose-related AEs.^4,25,28

Multimodal analgesia aims to reduce the risk for opioid-related AEs (ORAEs) and the impact of opioids on postsurgical milestones (eg, ambulation, discharge) and may reduce opioid consumption, with attendant reductions in ORAE risk.^29,30 Health economics studies have shown that postsurgical ORAEs are associated with increased hospital costs and LOS.⁶ In a study using a national hospital database, development of an ORAE (vs no ORAE) in postsurgical patients was associated with mean increases of about $4700 in hospital costs and 3.3 days in LOS.⁷ Reducing postsurgical opioid use may also help reduce the risk for opioid abuse, addiction, and diversion.^31-33

One approach to reducing opioid use involves continuous or intermittent administration of local anesthetics by elastomeric pumps to extend duration of postsurgical analgesia.^34-36 However, use of elastomeric pumps has been associated with risk for AEs, including tissue necrosis, sloughing, wound infection, and chondrolysis.^37-40 In addition, AEs related to “dose dumping” (accidental delivery of excessive doses) have been reported.^40-44 Key issues that may negatively affect rehabilitation after orthopedic surgery include consistency and accuracy of analgesic delivery and the potential for motor block–induced muscle weakness, which may lead to falls and constrain ambulation.^45-47

Liposome Bupivacaine

Description

Drug Delivery Technology. Liposome bupivacaine incorporates DepoFoam drug delivery technology (Pacira Pharmaceuticals, Inc.) to facilitate prolonged release of bupivacaine. This technology is based on creation of multivesicular liposome particles (diameter, 10-30 µm) with multiple aqueous chambers.^30,48 After administration into the surgical site, bupivacaine diffuses from chambers in the liposomal particles over time, providing analgesia and reduced opioid requirements for up to 72 hours.^29,30

Indication, Mechanism of Action, Pharmacokinetics, and Dose/Administration. Liposome bupivacaine is indicated for single-dose administration into the surgical site to produce postsurgical analgesia in patients at least 18 years old.¹⁴ Like other local anesthetics, liposome bupivacaine is thought to exert its pharmacologic effects by interacting with voltage-gated Na⁺ channels on neural membranes to raise the threshold for electrical excitability, to slow nerve impulse propagation, and to reduce the rate of rise of the action potential.^14,49

Liposome bupivacaine has dose-proportional pharmacokinetics.⁵⁰ Presence of a small amount of extra-liposomal bupivacaine in the formulation leads to a bimodal pharmacokinetic profile, with an initial peak serum concentration about 1 hour after administration, followed by a second peak within 12 to 36 hours (Figure).⁵⁰

Maximum amount of liposome bupivacaine approved for single administration is 266 mg (packaged as 20 mL of a 1.3% solution). However, product labeling includes safety data associated with doses of 532 mg or less.¹⁴ The appropriate volume to be used should be based on the amount required to cover the surgical area. Liposome bupivacaine may be expanded with preservative-free normal (0.9%) sterile saline to a total volume of 300 mL: 20 mL liposome bupivacaine plus 280 mL or less diluent, with final concentration of 0.89 mg/mL (1:14 by volume).¹⁴

A 25-gauge or larger bore needle should be used to slowly inject liposome bupivacaine into soft tissues of the surgical site, with frequent aspiration to check for blood to minimize risk for intravascular injection.¹⁴ Total volume used and fraction injected in specific regions of the surgical site depend on the procedure. For example, a TKA study used 266 mg diluted to a total volume of 60 mL, with 8 mL infiltrated to the area around the medial capsule, 8 mL around the lateral capsule, 12 mL around the posterior capsule, 8 mL around the peripatellar area, 12 mL into the capsulotomy incision, and 12 mL into the subcutaneous tissue on each side of the incision.⁵¹

Efficacy

Multiple Surgical Settings. The efficacy of liposome bupivacaine, either alone or as a component of a multimodal analgesic regimen, has been evaluated in a series of 10 phase 2 and 3 studies (8 active-controlled, 2 placebo-controlled) involving 823 patients undergoing TKA, bunionectomy, hemorrhoidectomy, inguinal hernia repair, or mammoplasty.⁵² Patients received a single liposome bupivacaine dose ranging from 66 to 532 mg.⁵²

Combined analyses of efficacy data from these studies found that liposome bupivacaine–based multimodal analgesic regimens produced postsurgical analgesia for up to 72 hours, increased time to first use of opioid rescue medication after surgery, and reduced total amount of postsurgical opioid consumption versus placebo.⁵²

Compared with standard of care, liposome bupivacaine has been shown to provide effective analgesia in open-label studies in patients undergoing open colectomy,⁵³ laparoscopic colectomy,⁵⁴ and ileostomy reversal,^55,56 as reflected in assessments of postsurgical opioid consumption, LOS, and hospital costs. It has also been studied when administered by infiltration into the transversus abdominis plane (TAP) in patients having laparoscopic prostatectomy and open abdominal hernia repair.^57,58

Orthopedic Surgery. In a phase 2 randomized, double-blind, dose-ranging study, TKA patients (N = 138) received bupivacaine HCl 150 mg or liposome bupivacaine 133, 266, 399, or 532 mg administered by local infiltration into the capsulotomy incision and on either side of the incision before wound closure.⁵¹ Postsurgical rescue analgesia was available to all patients. Cumulative pain intensity scores with activity (primary efficacy measure) were not statistically different between liposome bupivacaine groups and the bupivacaine HCl group through postoperative day 4. Mean scores in the liposome bupivacaine 266-, 399-, and 532-mg groups were numerically lower than for those treated with bupivacaine HCl on postoperative days 2 to 5, with all doses of liposome bupivacaine having a statistically significant lower pain score at rest on day 5. There were no statistically significant differences across treatment groups with respect to total amount of postsurgical opioids used.

In a phase 3 randomized, double-blind study of TKA patients (N = 245), liposome bupivacaine 532 mg administered into the surgical site was compared with bupivacaine HCl 200 mg for postsurgical analgesia.⁵² Rescue analgesia was available to all patients. No statistically significant between-group differences were found with respect to postsurgical cumulative pain scores through 72 hours (primary efficacy endpoint).

In a single-center retrospective TKA study, postsurgical outcomes in a patient cohort that received intraoperative periarticular infiltration with liposome bupivacaine 266 mg (n = 65) were compared with a cohort that received infiltration with a combination of ropivacaine 400 mg, morphine 5 mg, and epinephrine 0.4 mg (n = 85).⁵⁹ Patient-reported postsurgical pain scores were similar in the 2 treatment groups during the first 24 hours after surgery and at discharge. Mean (SD) pain scores during hospitalization after the first 24 hours until discharge were significantly (P = .04) higher in the liposome bupivacaine group, 4.9 (1.4), than in the periarticular group, 4.4 (1.6). There was no significant difference between the 2 treatment groups in postsurgical opioid use. The study demonstrated no advantage to using liposome bupivacaine injections with respect to pain relief, but it was a retrospective review in which pain scores were obtained from electronic medical records. It is essential that liposome bupivacaine be compared with intra-articular injections in well-designed randomized trials.

Another single-center, matched-cohort TKA study (N = 200) compared a liposome bupivacaine regimen with femoral nerve block.⁶⁰ Compared with patients who received femoral nerve block, patients who received liposome bupivacaine reported lower pain intensity scores after surgery and had shorter LOS, reduced costs, and improved knee flexion at follow-up.⁶⁰

Results from 2 other studies were presented at the 2014 meeting of the American Academy of Orthopaedic Surgeons (AAOS). One was a single-center, matched-cohort TKA study (N = 72) comparing infiltration of a single dose of liposome bupivacaine into the surgical site with continuous femoral nerve block.⁶¹ The 2 treatment groups had similar mean postsurgical pain intensity scores on a 0-to-10 visual analog scale, 1.8 for liposome bupivacaine and 2.3 for continuous nerve block (P = NS), but total amount of postsurgical opioids (hydrocodone-equivalent milligrams) was significantly (P < .0001) less in the liposome bupivacaine group (82 vs 177 mg).

The other study presented at the AAOS meeting was a larger, prospective case–control study comparing outcomes between 1000 patients who had total joint arthroplasty (TJA) with liposome bupivacaine and 1000 control patients who had TJA without liposome bupivacaine.⁶² For the control and liposome bupivacaine cohorts, respectively, mean postsurgical pain intensity scores were 2.41 and 1.98 (P < .0001), mean LOS was 2.83 days and 2.66 days (P < .02), and incidence of falls was 1.0% and 0.2% (P = .02). Average per-patient costs were $1246 lower in the liposome bupivacaine cohort.

A pivotal phase 3 placebo-controlled study compared liposome bupivacaine 106 mg with placebo in patients undergoing bunionectomy (N = 193).⁵ Rescue medication was available to all patients. Cumulative pain scores were significantly (P = .0005) lower in the liposome bupivacaine group (125) than in the placebo group (146) through 24 hours after surgery (primary efficacy measure) and significantly (P = .0229) lower (197 vs 220) through 36 hours. Median time to first use of rescue opioids was delayed in favor of the liposome bupivacaine group (7.2 vs 4.3 hours; P < .0001). Mean total number of opioid tablets used within 24 hours after surgery was also significantly lower (3.8 vs 4.7; P = .008), and a larger percentage of patients in the liposome bupivacaine group avoided opioid use altogether through 24 hours (7% vs 1%; P = .04).

Efficacy data for liposome bupivacaine appear promising for relief of pain after joint arthroplasty and other orthopedic procedures but have their limitations. First, no randomized trials have compared liposome bupivacaine with locally injected pain medications (intra-articular injections in TKA or hip arthroplasty). As these injections are quite common now, such analyses are essential. Second, cost-effectiveness studies are needed for orthopedic procedures. Third, most of the published studies were sponsored by the manufacturer of liposome bupivacaine—a situation that raises questions about potential bias. Non-industry-sponsored randomized trials assessing efficacy, safety, and cost-effectiveness are needed.

Safety

Local anesthetics, including liposome bupivacaine, have the potential for central nervous system (CNS) or cardiac toxicity resulting from excessive systemic absorption or inadvertent IV administration.⁶³ However, reported serious CNS or cardiac-related AEs are rare.^63,64

AE Profile. Safety data from 10 phase 2 and 3 studies involving 823 patients who received liposome bupivacaine were evaluated.⁶⁵ Of these patients, 545 received a dose of 266 mg or less (maximum dose approved by the US Food and Drug Administration [FDA]). Liposome bupivacaine was generally well tolerated. Reported AE incidence was 62% (liposome bupivacaine), 75% (bupivacaine HCl), and 43% (placebo). More than 90% of reported AEs were mild or moderate. The most frequently reported AEs were nausea, constipation, and vomiting (liposome bupivacaine, bupivacaine HCl) and nausea, dizziness, and vomiting (placebo).

Serious AEs were reported in 22 (2.7%) of the 823 patients in the liposome bupivacaine group, 24 (5.4%) of the 446 in the bupivacaine HCl group, and 2 (1.1%) of the 190 in the placebo group.⁶⁵ None of the serious AEs in the liposome bupivacaine and placebo groups were considered treatment-related. Six patients in the bupivacaine HCl group had treatment-related serious AEs (hypoglycemia, arthrofibrosis, hemarthrosis, joint swelling, scar, knee arthroplasty).

Cardiac Safety. Possible cardiac effects associated with liposome bupivacaine were evaluated with data from studies conducted during the clinical development program.⁶⁶ One hundred thirty-eight patients participated in the phase 2 safety and efficacy study in TKA. In these patients, a consistent change in mean heart rate (range, +12.2 to +16.5 beats per minute) was found across all liposome bupivacaine doses and with bupivacaine HCl. No clinically relevant changes from baseline in mean electrocardiographic parameters, including QTcF interval (QT interval adjusted using Fridericia’s correction formula), were found. In another analysis,⁶⁷ liposome bupivacaine administered in a single subcutaneous dose (266, 399, 532, or 665 mg) to healthy volunteers did not prolong (vs placebo) QTc interval.

Wound Healing. The potential effects of liposome bupivacaine on wound healing were evaluated with results from 10 phase 2 and 3 studies.⁶⁸ The assessments, which varied across studies, included clinicians’ overall satisfaction with patient wound healing, wound status assessment (categories included erythema, drainage, edema, and induration), and wound scarring (categories included pigmentation, height, pliability, and vascularity). Clinician-assessed scores reflected high satisfaction with wound healing overall. There were few statistically significant differences in wound status assessments between liposome bupivacaine and the comparators and no statistically significant differences in scarring between liposome bupivacaine and bupivacaine HCl.

The potential of liposome bupivacaine to have adverse intra-articular effects was assessed with drainage samples from patients (n = 23) who had TKA and received liposome bupivacaine (133, 266, 399, or 532 mg) or bupivacaine HCl (150 mg) by wound infiltration near the intra-articular space.^51,65 Only small amounts of bupivacaine were present in drainage fluid collected for 12 hours after liposome bupivacaine administration, comparable to bupivacaine HCl administration.⁶⁵ Currently, the product is not approved for intra-articular use.

Compatibility With Diluents, Other Medications, and Implant Materials

Liposome bupivacaine may be expanded up to a ratio of 1:14 by volume (to a final total volume of 300 mL or a concentration of 0.89 mg/mL) using preservative-free normal (0.9%) sterile saline for injection.¹⁴ It has also been shown in vitro to be compatible with lactated Ringer solution as a diluent.⁶⁹

Liposome bupivacaine should not be admixed with other medications before administration.¹⁴ No formal drug–drug interaction studies have been conducted with liposome bupivacaine, but it has been shown in vitro to be compatible with epinephrine solutions, with certain anti-infective medications (eg, bacitracin, gentamicin, cefazolin, cefuroxime), with certain analgesics (eg, ketorolac, morphine), with an antihypertensive medication (clonidine), with an antihemorrhagic medication (tranexamic acid), and with certain corticosteroids (eg, methylprednisolone, triamcinolone acetonide). These medications may be coadministered in the same location as liposome bupivacaine.⁶⁹

Topical antiseptics (eg, povidone iodine) may be used in surgical procedures involving liposome bupivacaine as long as they are not directly mixed with liposome bupivacaine and are allowed to dry before it is administered. If a topical antiseptic is used for wound irrigation, the wound should be rinsed clear before liposome bupivacaine administration.^14,69

Liposome bupivacaine may be coadministered into the same surgical site immediately after bupivacaine HCl as long as the dose ratio of liposome bupivacaine to bupivacaine HCl is 2:1 or higher. Because of the prolonged-release pharmacokinetic profile of liposome bupivacaine and the potential for increased bupivacaine exposure, bupivacaine HCl should not be administered within 96 hours after administration of liposome bupivacaine.^14,69

In vitro coincubation studies of liposome bupivacaine and other local anesthetics, including ropivacaine, lidocaine, and mepivacaine, have found rapid release of free bupivacaine from the liposome matrix. Therefore, after giving any of these other local anesthetics, surgeons should wait at least 20 minutes before administering liposome bupivacaine into the same area.^14,69

In vitro studies have shown that liposome bupivacaine is compatible with a wide range of commonly used implant materials, including polypropylene, expanded polytetrafluoroethylene, stainless steel, titanium, and smooth- and textured-type silicone.⁶⁹

Investigational Use and Ongoing Studies

A phase 2 randomized, double-masked, dose-escalating/deescalating study was conducted to evaluate the efficacy, safety, and pharmacokinetics of liposome bupivacaine (155, 199, or 310 mg) in comparison with bupivacaine HCl 125 mg for ankle nerve block in patients undergoing bunionectomy (N = 58).⁷⁰ The study medication was injected into 3 sites to reach the posterior tibial, sural, deep peroneal, superficial peroneal, and saphenous nerves. Pharmacokinetic exposure was higher for liposome bupivacaine than for bupivacaine HCl, as reflected by a significantly greater area under the curve, lower C_max (maximum serum concentration), and longer mean half-life. Mean pain intensity scores were lower in the bupivacaine HCl group than in each liposome bupivacaine group the first 12 hours after surgery. However, the liposome bupivacaine 310-mg group had similar or lower scores than the bupivacaine HCl group from 12 to 96 hours after surgery. The most common AEs in the liposome bupivacaine group were gastrointestinal and not treatment-related.⁷⁰

The efficacy and safety of liposome bupivacaine, administered as a femoral nerve block for postsurgical analgesia, were assessed in a phase 2/3 manufacturer-sponsored, placebo-controlled, multicenter, randomized, double-blind 2-part study (NCT01683071)⁷¹ in 280 TKA patients.^71,72 Part 2 of the study, comparing liposome bupivacaine 266 mg (n = 116) and placebo (n = 116), met its primary endpoint, demonstrating statistical significance in favor of liposome bupivacaine for cumulative pain scores over 72 hours (P < .0001), with decreased opioid use (P < .05) and a safety profile similar to that of placebo.⁷²

Other ongoing investigator-sponsored studies in orthopedic populations include comparisons of liposome bupivacaine and bupivacaine HCl for ultrasound-guided periarticular hip infiltration in hip arthroplasty (NTC01917191),⁷³ as femoral nerve block in TKA (NCT01977339),⁷⁴ and as interscalene brachial plexus block in arthroscopic shoulder surgery (NCT01977352).⁷⁵ The primary efficacy outcome measure in these studies was postsurgical opioid use.^73-75

Health Economics

A series of phase 4 health economics studies was conducted for gastrointestinal surgeries, including open colectomy, laparoscopic colectomy, and ileostomy reversal.^53-56,76 These studies, of similar design, showed that a liposome bupivacaine–based multimodal analgesic regimen was associated with reduced opioid use, shorter hospital LOS, and lower hospitalization costs in comparison with a traditional opioid-based regimen.^53-56 Although pooled analysis of these studies showed a cost savings of more than $2000 per patient and an LOS decrease of 1.4 days,⁷⁶ all were conducted in the gastrointestinal surgery setting. Studies are needed to fully assess the economic benefits associated with liposome bupivacaine in the orthopedic surgery setting.

Conclusion

Liposome bupivacaine represents a potentially important contributor to multimodal analgesic regimens used to manage postsurgical pain. Liposome bupivacaine has demonstrated efficacy in providing prolonged postsurgical analgesia and reducing postsurgical opioid use in most surgical settings studied. Additional data from health economics studies in gastrointestinal surgery suggest liposome bupivacaine–based multimodal analgesic regimens may also contribute to reductions in hospital LOS and hospitalization costs. Non-industry-sponsored trials are needed to answer these crucial questions in orthopedic surgery settings. Nevertheless, data on the safety and efficacy of liposome bupivacaine for postsurgical analgesia continue to accumulate, and liposome bupivacaine appears to be a feasible therapeutic option for managing postsurgical pain in orthopedic surgery.

Approximately 5.5 million patients undergo orthopedic surgery in the United States each year, and more than 1 million of the procedures are total knee arthroplasty (TKA) or total hip arthroplasty.¹ From its 2010 level, demand for joint arthroplasty is expected to double by 2020 and quadruple by 2030.²

About half the patients who have major joint arthroplasty experience severe postsurgical pain.³ Because postsurgical pain may persist for days or weeks, and inadequate treatment is associated with negative outcomes, achieving effective postsurgical analgesia is an important consideration.^4-7 Complications of inadequate postsurgical pain management include thromboembolic or pulmonary complications, development of chronic pain, and decrements in health-related quality of life.^4,8

In patients who have orthopedic surgery, the inability to adequately control postsurgical pain has been associated with increased hospital length of stay (LOS), delayed time to ambulation, and reduced capacity for exercise.^9-12 A recent study involving 4709 patients who had hip or knee arthroplasty found that postsurgical pain relief was the second most highly correlated factor with respect to overall patient satisfaction (how well surgery met patient expectations was the most highly correlated factor),¹³ suggesting that postsurgical analgesia should be a focus of surgical practice.

A prolonged-release liposomal formulation of the local anesthetic bupivacaine is now available. Bupivacaine liposome injectable suspension (Exparel; Pacira Pharmaceuticals, Inc., Parsippany, New Jersey) is indicated for administration into the surgical site to produce postsurgical analgesia.¹⁴ In this article, we review evidence from clinical studies regarding the potential contribution of liposome bupivacaine to improving postsurgical pain management when used as part of a multimodal analgesic regimen in patients undergoing orthopedic surgery.

Postsurgical Pain Management in Orthopedic Surgery

Frequently Used Modalities

Analgesic modalities commonly used for perioperative pain management include central (eg, epidural),^4,10,15,16 central regional (eg, neuraxial),⁴ peripheral regional (eg, peripheral nerve blocks, local/regional surgical site infiltration, intra-articular administration),^{4,10,15,17-25} and intravenous (IV) patient-controlled analgesia.^4,10,25 These pharmacologic interventions may be augmented by nonpharmacologic modalities (eg, transcutaneous electrical nerve stimulation).²⁶

Pharmacologic treatment options for perioperative pain management include opioids, local anesthetics, clonidine, ketamine, nonsteroidal anti-inflammatory drugs, acetaminophen, and calcium-channel blockers.^4,26-28 In TKA, “drug cocktails” (eg, combinations of ropivacaine, ketorolac, epinephrine, and clonidine) for regional or intra-articular injection can also provide effective immediate postsurgical analgesia.²⁵ Although opioids are the most commonly used analgesics for management of orthopedic perioperative pain,²⁵ their use is often associated with adverse effects (AEs), including constipation or ileus, nausea, sedation, dizziness, pruritus, urinary retention, and respiratory depression.⁶

Multimodal Analgesic Regimens for Postsurgical Pain Management

Current American Society of Anesthesiologists guidelines endorse use of multimodal analgesia, whenever possible, to provide effective management of acute perioperative pain.⁴ Multimodal analgesia involves applying 2 or more agents with different mechanisms of action to achieve a synergistic effect, which allows each agent to be reduced in dose^4,28 and thereby may limit the risk and severity of dose-related AEs.^4,25,28

Multimodal analgesia aims to reduce the risk for opioid-related AEs (ORAEs) and the impact of opioids on postsurgical milestones (eg, ambulation, discharge) and may reduce opioid consumption, with attendant reductions in ORAE risk.^29,30 Health economics studies have shown that postsurgical ORAEs are associated with increased hospital costs and LOS.⁶ In a study using a national hospital database, development of an ORAE (vs no ORAE) in postsurgical patients was associated with mean increases of about $4700 in hospital costs and 3.3 days in LOS.⁷ Reducing postsurgical opioid use may also help reduce the risk for opioid abuse, addiction, and diversion.^31-33

One approach to reducing opioid use involves continuous or intermittent administration of local anesthetics by elastomeric pumps to extend duration of postsurgical analgesia.^34-36 However, use of elastomeric pumps has been associated with risk for AEs, including tissue necrosis, sloughing, wound infection, and chondrolysis.^37-40 In addition, AEs related to “dose dumping” (accidental delivery of excessive doses) have been reported.^40-44 Key issues that may negatively affect rehabilitation after orthopedic surgery include consistency and accuracy of analgesic delivery and the potential for motor block–induced muscle weakness, which may lead to falls and constrain ambulation.^45-47

Liposome Bupivacaine

Description

Drug Delivery Technology. Liposome bupivacaine incorporates DepoFoam drug delivery technology (Pacira Pharmaceuticals, Inc.) to facilitate prolonged release of bupivacaine. This technology is based on creation of multivesicular liposome particles (diameter, 10-30 µm) with multiple aqueous chambers.^30,48 After administration into the surgical site, bupivacaine diffuses from chambers in the liposomal particles over time, providing analgesia and reduced opioid requirements for up to 72 hours.^29,30

Indication, Mechanism of Action, Pharmacokinetics, and Dose/Administration. Liposome bupivacaine is indicated for single-dose administration into the surgical site to produce postsurgical analgesia in patients at least 18 years old.¹⁴ Like other local anesthetics, liposome bupivacaine is thought to exert its pharmacologic effects by interacting with voltage-gated Na⁺ channels on neural membranes to raise the threshold for electrical excitability, to slow nerve impulse propagation, and to reduce the rate of rise of the action potential.^14,49

Liposome bupivacaine has dose-proportional pharmacokinetics.⁵⁰ Presence of a small amount of extra-liposomal bupivacaine in the formulation leads to a bimodal pharmacokinetic profile, with an initial peak serum concentration about 1 hour after administration, followed by a second peak within 12 to 36 hours (Figure).⁵⁰

Maximum amount of liposome bupivacaine approved for single administration is 266 mg (packaged as 20 mL of a 1.3% solution). However, product labeling includes safety data associated with doses of 532 mg or less.¹⁴ The appropriate volume to be used should be based on the amount required to cover the surgical area. Liposome bupivacaine may be expanded with preservative-free normal (0.9%) sterile saline to a total volume of 300 mL: 20 mL liposome bupivacaine plus 280 mL or less diluent, with final concentration of 0.89 mg/mL (1:14 by volume).¹⁴

A 25-gauge or larger bore needle should be used to slowly inject liposome bupivacaine into soft tissues of the surgical site, with frequent aspiration to check for blood to minimize risk for intravascular injection.¹⁴ Total volume used and fraction injected in specific regions of the surgical site depend on the procedure. For example, a TKA study used 266 mg diluted to a total volume of 60 mL, with 8 mL infiltrated to the area around the medial capsule, 8 mL around the lateral capsule, 12 mL around the posterior capsule, 8 mL around the peripatellar area, 12 mL into the capsulotomy incision, and 12 mL into the subcutaneous tissue on each side of the incision.⁵¹

Efficacy

Multiple Surgical Settings. The efficacy of liposome bupivacaine, either alone or as a component of a multimodal analgesic regimen, has been evaluated in a series of 10 phase 2 and 3 studies (8 active-controlled, 2 placebo-controlled) involving 823 patients undergoing TKA, bunionectomy, hemorrhoidectomy, inguinal hernia repair, or mammoplasty.⁵² Patients received a single liposome bupivacaine dose ranging from 66 to 532 mg.⁵²

Combined analyses of efficacy data from these studies found that liposome bupivacaine–based multimodal analgesic regimens produced postsurgical analgesia for up to 72 hours, increased time to first use of opioid rescue medication after surgery, and reduced total amount of postsurgical opioid consumption versus placebo.⁵²

Compared with standard of care, liposome bupivacaine has been shown to provide effective analgesia in open-label studies in patients undergoing open colectomy,⁵³ laparoscopic colectomy,⁵⁴ and ileostomy reversal,^55,56 as reflected in assessments of postsurgical opioid consumption, LOS, and hospital costs. It has also been studied when administered by infiltration into the transversus abdominis plane (TAP) in patients having laparoscopic prostatectomy and open abdominal hernia repair.^57,58

Orthopedic Surgery. In a phase 2 randomized, double-blind, dose-ranging study, TKA patients (N = 138) received bupivacaine HCl 150 mg or liposome bupivacaine 133, 266, 399, or 532 mg administered by local infiltration into the capsulotomy incision and on either side of the incision before wound closure.⁵¹ Postsurgical rescue analgesia was available to all patients. Cumulative pain intensity scores with activity (primary efficacy measure) were not statistically different between liposome bupivacaine groups and the bupivacaine HCl group through postoperative day 4. Mean scores in the liposome bupivacaine 266-, 399-, and 532-mg groups were numerically lower than for those treated with bupivacaine HCl on postoperative days 2 to 5, with all doses of liposome bupivacaine having a statistically significant lower pain score at rest on day 5. There were no statistically significant differences across treatment groups with respect to total amount of postsurgical opioids used.

In a phase 3 randomized, double-blind study of TKA patients (N = 245), liposome bupivacaine 532 mg administered into the surgical site was compared with bupivacaine HCl 200 mg for postsurgical analgesia.⁵² Rescue analgesia was available to all patients. No statistically significant between-group differences were found with respect to postsurgical cumulative pain scores through 72 hours (primary efficacy endpoint).

In a single-center retrospective TKA study, postsurgical outcomes in a patient cohort that received intraoperative periarticular infiltration with liposome bupivacaine 266 mg (n = 65) were compared with a cohort that received infiltration with a combination of ropivacaine 400 mg, morphine 5 mg, and epinephrine 0.4 mg (n = 85).⁵⁹ Patient-reported postsurgical pain scores were similar in the 2 treatment groups during the first 24 hours after surgery and at discharge. Mean (SD) pain scores during hospitalization after the first 24 hours until discharge were significantly (P = .04) higher in the liposome bupivacaine group, 4.9 (1.4), than in the periarticular group, 4.4 (1.6). There was no significant difference between the 2 treatment groups in postsurgical opioid use. The study demonstrated no advantage to using liposome bupivacaine injections with respect to pain relief, but it was a retrospective review in which pain scores were obtained from electronic medical records. It is essential that liposome bupivacaine be compared with intra-articular injections in well-designed randomized trials.

Another single-center, matched-cohort TKA study (N = 200) compared a liposome bupivacaine regimen with femoral nerve block.⁶⁰ Compared with patients who received femoral nerve block, patients who received liposome bupivacaine reported lower pain intensity scores after surgery and had shorter LOS, reduced costs, and improved knee flexion at follow-up.⁶⁰

Results from 2 other studies were presented at the 2014 meeting of the American Academy of Orthopaedic Surgeons (AAOS). One was a single-center, matched-cohort TKA study (N = 72) comparing infiltration of a single dose of liposome bupivacaine into the surgical site with continuous femoral nerve block.⁶¹ The 2 treatment groups had similar mean postsurgical pain intensity scores on a 0-to-10 visual analog scale, 1.8 for liposome bupivacaine and 2.3 for continuous nerve block (P = NS), but total amount of postsurgical opioids (hydrocodone-equivalent milligrams) was significantly (P < .0001) less in the liposome bupivacaine group (82 vs 177 mg).

The other study presented at the AAOS meeting was a larger, prospective case–control study comparing outcomes between 1000 patients who had total joint arthroplasty (TJA) with liposome bupivacaine and 1000 control patients who had TJA without liposome bupivacaine.⁶² For the control and liposome bupivacaine cohorts, respectively, mean postsurgical pain intensity scores were 2.41 and 1.98 (P < .0001), mean LOS was 2.83 days and 2.66 days (P < .02), and incidence of falls was 1.0% and 0.2% (P = .02). Average per-patient costs were $1246 lower in the liposome bupivacaine cohort.

A pivotal phase 3 placebo-controlled study compared liposome bupivacaine 106 mg with placebo in patients undergoing bunionectomy (N = 193).⁵ Rescue medication was available to all patients. Cumulative pain scores were significantly (P = .0005) lower in the liposome bupivacaine group (125) than in the placebo group (146) through 24 hours after surgery (primary efficacy measure) and significantly (P = .0229) lower (197 vs 220) through 36 hours. Median time to first use of rescue opioids was delayed in favor of the liposome bupivacaine group (7.2 vs 4.3 hours; P < .0001). Mean total number of opioid tablets used within 24 hours after surgery was also significantly lower (3.8 vs 4.7; P = .008), and a larger percentage of patients in the liposome bupivacaine group avoided opioid use altogether through 24 hours (7% vs 1%; P = .04).

Efficacy data for liposome bupivacaine appear promising for relief of pain after joint arthroplasty and other orthopedic procedures but have their limitations. First, no randomized trials have compared liposome bupivacaine with locally injected pain medications (intra-articular injections in TKA or hip arthroplasty). As these injections are quite common now, such analyses are essential. Second, cost-effectiveness studies are needed for orthopedic procedures. Third, most of the published studies were sponsored by the manufacturer of liposome bupivacaine—a situation that raises questions about potential bias. Non-industry-sponsored randomized trials assessing efficacy, safety, and cost-effectiveness are needed.

Safety

Local anesthetics, including liposome bupivacaine, have the potential for central nervous system (CNS) or cardiac toxicity resulting from excessive systemic absorption or inadvertent IV administration.⁶³ However, reported serious CNS or cardiac-related AEs are rare.^63,64

AE Profile. Safety data from 10 phase 2 and 3 studies involving 823 patients who received liposome bupivacaine were evaluated.⁶⁵ Of these patients, 545 received a dose of 266 mg or less (maximum dose approved by the US Food and Drug Administration [FDA]). Liposome bupivacaine was generally well tolerated. Reported AE incidence was 62% (liposome bupivacaine), 75% (bupivacaine HCl), and 43% (placebo). More than 90% of reported AEs were mild or moderate. The most frequently reported AEs were nausea, constipation, and vomiting (liposome bupivacaine, bupivacaine HCl) and nausea, dizziness, and vomiting (placebo).

Serious AEs were reported in 22 (2.7%) of the 823 patients in the liposome bupivacaine group, 24 (5.4%) of the 446 in the bupivacaine HCl group, and 2 (1.1%) of the 190 in the placebo group.⁶⁵ None of the serious AEs in the liposome bupivacaine and placebo groups were considered treatment-related. Six patients in the bupivacaine HCl group had treatment-related serious AEs (hypoglycemia, arthrofibrosis, hemarthrosis, joint swelling, scar, knee arthroplasty).

Cardiac Safety. Possible cardiac effects associated with liposome bupivacaine were evaluated with data from studies conducted during the clinical development program.⁶⁶ One hundred thirty-eight patients participated in the phase 2 safety and efficacy study in TKA. In these patients, a consistent change in mean heart rate (range, +12.2 to +16.5 beats per minute) was found across all liposome bupivacaine doses and with bupivacaine HCl. No clinically relevant changes from baseline in mean electrocardiographic parameters, including QTcF interval (QT interval adjusted using Fridericia’s correction formula), were found. In another analysis,⁶⁷ liposome bupivacaine administered in a single subcutaneous dose (266, 399, 532, or 665 mg) to healthy volunteers did not prolong (vs placebo) QTc interval.

Wound Healing. The potential effects of liposome bupivacaine on wound healing were evaluated with results from 10 phase 2 and 3 studies.⁶⁸ The assessments, which varied across studies, included clinicians’ overall satisfaction with patient wound healing, wound status assessment (categories included erythema, drainage, edema, and induration), and wound scarring (categories included pigmentation, height, pliability, and vascularity). Clinician-assessed scores reflected high satisfaction with wound healing overall. There were few statistically significant differences in wound status assessments between liposome bupivacaine and the comparators and no statistically significant differences in scarring between liposome bupivacaine and bupivacaine HCl.

The potential of liposome bupivacaine to have adverse intra-articular effects was assessed with drainage samples from patients (n = 23) who had TKA and received liposome bupivacaine (133, 266, 399, or 532 mg) or bupivacaine HCl (150 mg) by wound infiltration near the intra-articular space.^51,65 Only small amounts of bupivacaine were present in drainage fluid collected for 12 hours after liposome bupivacaine administration, comparable to bupivacaine HCl administration.⁶⁵ Currently, the product is not approved for intra-articular use.

Compatibility With Diluents, Other Medications, and Implant Materials

Liposome bupivacaine may be expanded up to a ratio of 1:14 by volume (to a final total volume of 300 mL or a concentration of 0.89 mg/mL) using preservative-free normal (0.9%) sterile saline for injection.¹⁴ It has also been shown in vitro to be compatible with lactated Ringer solution as a diluent.⁶⁹

Liposome bupivacaine should not be admixed with other medications before administration.¹⁴ No formal drug–drug interaction studies have been conducted with liposome bupivacaine, but it has been shown in vitro to be compatible with epinephrine solutions, with certain anti-infective medications (eg, bacitracin, gentamicin, cefazolin, cefuroxime), with certain analgesics (eg, ketorolac, morphine), with an antihypertensive medication (clonidine), with an antihemorrhagic medication (tranexamic acid), and with certain corticosteroids (eg, methylprednisolone, triamcinolone acetonide). These medications may be coadministered in the same location as liposome bupivacaine.⁶⁹

Topical antiseptics (eg, povidone iodine) may be used in surgical procedures involving liposome bupivacaine as long as they are not directly mixed with liposome bupivacaine and are allowed to dry before it is administered. If a topical antiseptic is used for wound irrigation, the wound should be rinsed clear before liposome bupivacaine administration.^14,69

Liposome bupivacaine may be coadministered into the same surgical site immediately after bupivacaine HCl as long as the dose ratio of liposome bupivacaine to bupivacaine HCl is 2:1 or higher. Because of the prolonged-release pharmacokinetic profile of liposome bupivacaine and the potential for increased bupivacaine exposure, bupivacaine HCl should not be administered within 96 hours after administration of liposome bupivacaine.^14,69

In vitro coincubation studies of liposome bupivacaine and other local anesthetics, including ropivacaine, lidocaine, and mepivacaine, have found rapid release of free bupivacaine from the liposome matrix. Therefore, after giving any of these other local anesthetics, surgeons should wait at least 20 minutes before administering liposome bupivacaine into the same area.^14,69

In vitro studies have shown that liposome bupivacaine is compatible with a wide range of commonly used implant materials, including polypropylene, expanded polytetrafluoroethylene, stainless steel, titanium, and smooth- and textured-type silicone.⁶⁹

Investigational Use and Ongoing Studies

A phase 2 randomized, double-masked, dose-escalating/deescalating study was conducted to evaluate the efficacy, safety, and pharmacokinetics of liposome bupivacaine (155, 199, or 310 mg) in comparison with bupivacaine HCl 125 mg for ankle nerve block in patients undergoing bunionectomy (N = 58).⁷⁰ The study medication was injected into 3 sites to reach the posterior tibial, sural, deep peroneal, superficial peroneal, and saphenous nerves. Pharmacokinetic exposure was higher for liposome bupivacaine than for bupivacaine HCl, as reflected by a significantly greater area under the curve, lower C_max (maximum serum concentration), and longer mean half-life. Mean pain intensity scores were lower in the bupivacaine HCl group than in each liposome bupivacaine group the first 12 hours after surgery. However, the liposome bupivacaine 310-mg group had similar or lower scores than the bupivacaine HCl group from 12 to 96 hours after surgery. The most common AEs in the liposome bupivacaine group were gastrointestinal and not treatment-related.⁷⁰

The efficacy and safety of liposome bupivacaine, administered as a femoral nerve block for postsurgical analgesia, were assessed in a phase 2/3 manufacturer-sponsored, placebo-controlled, multicenter, randomized, double-blind 2-part study (NCT01683071)⁷¹ in 280 TKA patients.^71,72 Part 2 of the study, comparing liposome bupivacaine 266 mg (n = 116) and placebo (n = 116), met its primary endpoint, demonstrating statistical significance in favor of liposome bupivacaine for cumulative pain scores over 72 hours (P < .0001), with decreased opioid use (P < .05) and a safety profile similar to that of placebo.⁷²

Other ongoing investigator-sponsored studies in orthopedic populations include comparisons of liposome bupivacaine and bupivacaine HCl for ultrasound-guided periarticular hip infiltration in hip arthroplasty (NTC01917191),⁷³ as femoral nerve block in TKA (NCT01977339),⁷⁴ and as interscalene brachial plexus block in arthroscopic shoulder surgery (NCT01977352).⁷⁵ The primary efficacy outcome measure in these studies was postsurgical opioid use.^73-75

Health Economics

A series of phase 4 health economics studies was conducted for gastrointestinal surgeries, including open colectomy, laparoscopic colectomy, and ileostomy reversal.^53-56,76 These studies, of similar design, showed that a liposome bupivacaine–based multimodal analgesic regimen was associated with reduced opioid use, shorter hospital LOS, and lower hospitalization costs in comparison with a traditional opioid-based regimen.^53-56 Although pooled analysis of these studies showed a cost savings of more than $2000 per patient and an LOS decrease of 1.4 days,⁷⁶ all were conducted in the gastrointestinal surgery setting. Studies are needed to fully assess the economic benefits associated with liposome bupivacaine in the orthopedic surgery setting.

Conclusion

Liposome bupivacaine represents a potentially important contributor to multimodal analgesic regimens used to manage postsurgical pain. Liposome bupivacaine has demonstrated efficacy in providing prolonged postsurgical analgesia and reducing postsurgical opioid use in most surgical settings studied. Additional data from health economics studies in gastrointestinal surgery suggest liposome bupivacaine–based multimodal analgesic regimens may also contribute to reductions in hospital LOS and hospitalization costs. Non-industry-sponsored trials are needed to answer these crucial questions in orthopedic surgery settings. Nevertheless, data on the safety and efficacy of liposome bupivacaine for postsurgical analgesia continue to accumulate, and liposome bupivacaine appears to be a feasible therapeutic option for managing postsurgical pain in orthopedic surgery.