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It sounds counterintuitive, but could touchscreen technology make HM more personal? Satish Misra, MD, thinks so. A first-year internal-medicine resident at Johns Hopkins School of Medicine in Baltimore, he also serves as a senior editor for iMedicalApps.com, a blog that publishes commentary and reviews of mobile medical technology and applications in the healthcare realm.

Dr. Misra envisions smartphones and tablet computers as a way of connecting more with patients. “It’s just a much more interactive platform than your standard keyboard and screen,” he says. “It’s something that’s easy to put in front of both myself and the patient, as opposed to between us. It sort of demystifies a lot of what you’re trying to say.

“You can imagine if you’re trying to explain endoscopy to a patient. It’s one thing to use yourself as an example … it’s another thing to have a 3-D image you can rotate with your finger and enlarge in certain places.”

Not all patients are ready to see those details, though. And that’s where other intangible lessons come in handy for hospitalists, says Steven Peskin, MD, MBA, FACP, executive vice president and chief medical officer of Yardley, Pa.-based MediMedia USA. He agrees there are times when the use of touchscreen technology to educate might enhance the patient encounter. But hospitalists need to use their judgment in deciding which patients can tolerate learning—for example, the exact path a catheterization tube takes on its way north from entry in that patient’s groin.

“Some might be scared to death; others might be reassured,” Dr. Peskin says. “The personalization is still largely in the personal skills, the very-old-school bedside manner.

The power of digital media to pictorially or visually or graphically show somebody something—sure, absolutely, that’s valuable. I wouldn’t equate that with patient-physician communication or healthcare professional communication. I think that still relies more on eye contact, empathy, and listening.”

Richard Quinn is a freelance writer based in New Jersey.

It sounds counterintuitive, but could touchscreen technology make HM more personal? Satish Misra, MD, thinks so. A first-year internal-medicine resident at Johns Hopkins School of Medicine in Baltimore, he also serves as a senior editor for iMedicalApps.com, a blog that publishes commentary and reviews of mobile medical technology and applications in the healthcare realm.

Dr. Misra envisions smartphones and tablet computers as a way of connecting more with patients. “It’s just a much more interactive platform than your standard keyboard and screen,” he says. “It’s something that’s easy to put in front of both myself and the patient, as opposed to between us. It sort of demystifies a lot of what you’re trying to say.

“You can imagine if you’re trying to explain endoscopy to a patient. It’s one thing to use yourself as an example … it’s another thing to have a 3-D image you can rotate with your finger and enlarge in certain places.”

Not all patients are ready to see those details, though. And that’s where other intangible lessons come in handy for hospitalists, says Steven Peskin, MD, MBA, FACP, executive vice president and chief medical officer of Yardley, Pa.-based MediMedia USA. He agrees there are times when the use of touchscreen technology to educate might enhance the patient encounter. But hospitalists need to use their judgment in deciding which patients can tolerate learning—for example, the exact path a catheterization tube takes on its way north from entry in that patient’s groin.

“Some might be scared to death; others might be reassured,” Dr. Peskin says. “The personalization is still largely in the personal skills, the very-old-school bedside manner.

The power of digital media to pictorially or visually or graphically show somebody something—sure, absolutely, that’s valuable. I wouldn’t equate that with patient-physician communication or healthcare professional communication. I think that still relies more on eye contact, empathy, and listening.”

Richard Quinn is a freelance writer based in New Jersey.

It sounds counterintuitive, but could touchscreen technology make HM more personal? Satish Misra, MD, thinks so. A first-year internal-medicine resident at Johns Hopkins School of Medicine in Baltimore, he also serves as a senior editor for iMedicalApps.com, a blog that publishes commentary and reviews of mobile medical technology and applications in the healthcare realm.

Dr. Misra envisions smartphones and tablet computers as a way of connecting more with patients. “It’s just a much more interactive platform than your standard keyboard and screen,” he says. “It’s something that’s easy to put in front of both myself and the patient, as opposed to between us. It sort of demystifies a lot of what you’re trying to say.

“You can imagine if you’re trying to explain endoscopy to a patient. It’s one thing to use yourself as an example … it’s another thing to have a 3-D image you can rotate with your finger and enlarge in certain places.”

Not all patients are ready to see those details, though. And that’s where other intangible lessons come in handy for hospitalists, says Steven Peskin, MD, MBA, FACP, executive vice president and chief medical officer of Yardley, Pa.-based MediMedia USA. He agrees there are times when the use of touchscreen technology to educate might enhance the patient encounter. But hospitalists need to use their judgment in deciding which patients can tolerate learning—for example, the exact path a catheterization tube takes on its way north from entry in that patient’s groin.

“Some might be scared to death; others might be reassured,” Dr. Peskin says. “The personalization is still largely in the personal skills, the very-old-school bedside manner.

The power of digital media to pictorially or visually or graphically show somebody something—sure, absolutely, that’s valuable. I wouldn’t equate that with patient-physician communication or healthcare professional communication. I think that still relies more on eye contact, empathy, and listening.”

Richard Quinn is a freelance writer based in New Jersey.

Summit Director:
Amir K. Jaffer, MD

Contents

Summit Faculty

Summit Program

Abstract 1: Application of 2007 ACC/AHA guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery using decision support tools
BobbieJean Sweitzer, Michael Vigoda, Vicente Behrens, Nikola Miljkovic, and Kris Arheart

Abstract 2: Prevalence of obstructive dleep spnea in patients presenting for hip or knee replacement surgery
Micah Beachy, DO; Jason Shiffermiller, MD; and Chad Vokoun, MD

Abstract 3: A protocol to triage preoperative assessments to either nurses or nurse practitioners/physician assistants
Anthony Basil, RN; Pamela Pennigar, FNP; David R. Wright, MD; and Ronald P. Olson, MD

Abstract 4: Application of 2007 ACC/AHA guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery using decision support tools
BobbieJean Sweitzer, Michael Vigoda, Vicente Behrens, Nikola Miljkovic, and Kris Arheart

Abstract 5: Most anesthesiologists don’t correctly apply 2007 ACC/AHA guidelines on perioperative cardiac evaluation
BobbieJean Sweitzer, Michael Vigoda, Vicente Behrens, Nikola Miljkovic, Kris Arheart, and Richard Dutton

Abstract 6: Anesthesiology residents do not agree with their training programs on the degree to which the 2007 ACC/AHA guidelines are emphasized
BobbieJean Sweitzer, Michael Vigoda, Vicente Behrens, Nikola Miljkovic, and Kris Arheart

Abstract 7: Prevalence of obstructive sleep apnea in patients presenting for hip or knee replacement surgery
Micah Beachy, DO; Jason Shiffermiller, MD; and Chad Vokoun, MD

Abstract 8: A protocol to triage preoperative assessments to either nurses or nurse practitioners/physician assistants
Anthony Basil, RN; Pamela Pennigar, FNP; David R. Wright, MD; and Ronald P. Olson, MD

Abstract 9: Do ACEIs on the morning of surgery increase risk of intraoperative hypotension?
Steven L. Cohn, MD, and Kalia Skeete, MD

Abstract 10: One-year incidence of postoperative troponin revations in patients undergoing major orthopedic surgery
Michael Urban, MD, PhD; Stephen Wolfe, BS; Niel Sanghevi, BS; and Steven Magid, MD

Abstract 11: A review of preoperative clinic cardiology referrals for adults undergoing intermediate- and low-risk surgery
Susan Calderwood, MD; Jennifer Lee Morse, MS; and Damon R. Michaels, CCRP

Abstract 12: Patterns of preoperative consultation by risk and surgical specialty in a large health care system
Stephan Thilen, MD, MS; Christopher Bryson, MD, MS; Robert Reid, MD, PhD; and Miriam Treggiari, MD, MPH, PhD

Abstract 13: One-year incidence for admission to a critical care unit after major orthopedic surgery
Michael Urban, MD, PhD; Steven Magid, MD; and Michele Mangini, DNP

Abstract 14: Determination of the causes of long patient wait times in a preoperative evaluation clinic
Jean Kwo, MD; Devon Price, BS; Mary Elizabeth Ellbeg, RN; and Retsef Levi, PhD

Abstract 15: Does perioperative statin treatment affect hospital and ICU length of stay rollowing cardiac surgery: A systematic review
Vineet Chopra, MD, FACP, FHM; David Wesorick, MD; and Kim A. Eagle, MD

Abstract 16: Assessment of patient satisfaction of nurse screening vs complete preoperative assessment
Ronald Olson, MD, and Kathy Bock, RN

Abstract 17: Traumatic subdural hematoma: An update on morbidity
Rachel Thompson, MD; Christina Ryan, MD; Nancy Temkin, PhD; Richard Ellenbogen, MD; and Joann G. Elmore, MD, MPH

Abstract 18: Lipid emulsion as a lifesaving treatment for local anesthetic systemic toxicity (LAST)
Deepti Sachdev and Guy Weinberg, MD

Abstract 19: Perioperative ACLS recommendations should be modified for the treatment of local anesthetic toxicity
Adam Haas, MD, and Alexia Beccue, MD

Abstract 20: Preoperative EMR containing smart-set reminders improve accuracy of documentation by nonanesthesia clinicians during preoperative assessments
Angela Edwards, MD; Jill Grant, PA; and Ruth Hyde, MD

Abstract 21: POET: Procedure outcomes evaluation tool
Ahmad AbuSalah, MSc, and Terrence Adam, MD, PhD

Abstract 22: Results of a multidisciplinary preoperative assessment process for high-risk orthopedic patients
Terrence Adam, MD, PhD; Connie Parenti, MD; Terence Gioe, MD; and Karen Ringsred, MD

Abstract 23: Practical algorithm for preoperative evaluation of patients with liver disease
Madalina A. Vlase, PA-C, and Deborah C. Richman, MBChB, FFA(SA)

Abstract 24: Evaluation and management of isolated elevated aPTT
Sheila Hassan, MSN, NP; Patricia Kidik, MSN, NP; Catherine McGowan, MSN, NP; and Angela M. Bader, MD

Abstract 25: A perioperative triage plan for obstructive sleep apnea patients
Christian Altman, MD; R. Michael Boyer, DO; and Peter G. Kallas, MD

Abstract 26: Quantitative evaluation of handoff checklists
Jay Joshi, MD, and David Mayer, MD

Abstract 27: To deflate or not to deflate: Lap-Band® management in subsequent surgeries
Arjun Reddy, MD, and Deborah C. Richman, MBChB, FFA(SA)

Abstract 28: Takotsubo cardiomyopathy and resultant cardiogenic shock after mitral valve repair
Adam Evans, MD, MBA; Daniel B. Sims, MD; Nir Uriel, MD; Ulrich P. Jorde, MD; and Craig R. Smith, MD

Abstract 29: Intravenous vitamin K: Rapid reversal of warfarin and lack of subsequent warfarin resistance
Feras Abdul Khalek, MD; Interdeep Dhaliwal, MD; and Twylla Tassava, MD

Abstract 30: Cervical spine surgery: When not to extubate postoperatively
Carlos Mateo Mijares, MD; Doris Debs, ARNP, MSN-BC; Nicole Martin, MD; and Ronald Lee Samson, MD

Abstract 31: Total occlusion of oral cavity by mandibular sarcoma for resection: To intubate nasally or proceed to an awake tracheostomy?
Carlos Mateo Mijares, MD, and Maria DeLapena, MD

Abstract 32: Perioperative fatal embolic stroke associated with iron deficiency anemia and thrombocytosis
Carlos Mateo Mijares, MD; Nicole Martin, MD; and Ricardo Martinez-Ruiz, MD

Abstract 33: Conservative approach saves the day anesthesia-wise and surgical-wise
Carlos Mateo Mijares, MD; Bradley Shore, MD; Edward Zalkind, CRNA; and Nicole Martin, MD

Abstract 34: Predictors of acute kidney injury in patients undergoing total knee replacement surgery
Vishal Sehgal, MD; Pardeep Bansal, MD; Praveen Reddy, MD; Vishal Sharma, MD; Samuel Lesko, MD; John H. Doherty, MD; Theodore Tomaszewski, MD; Jack Prior, MD; Roger Getts, MD; and Jeremiah Eagan, MD

Abstract 35: Perioperative medical management of the Marfan patient undergoing repeat cardiothoracic surgery
Aashish Shah, MD, and Adam Skrzynski, MD

Index of abstract authors

Summit Director:
Amir K. Jaffer, MD

Contents

Summit Faculty

Summit Program

Abstract 1: Application of 2007 ACC/AHA guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery using decision support tools
BobbieJean Sweitzer, Michael Vigoda, Vicente Behrens, Nikola Miljkovic, and Kris Arheart

Abstract 2: Prevalence of obstructive dleep spnea in patients presenting for hip or knee replacement surgery
Micah Beachy, DO; Jason Shiffermiller, MD; and Chad Vokoun, MD

Abstract 3: A protocol to triage preoperative assessments to either nurses or nurse practitioners/physician assistants
Anthony Basil, RN; Pamela Pennigar, FNP; David R. Wright, MD; and Ronald P. Olson, MD

Abstract 4: Application of 2007 ACC/AHA guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery using decision support tools
BobbieJean Sweitzer, Michael Vigoda, Vicente Behrens, Nikola Miljkovic, and Kris Arheart

Abstract 5: Most anesthesiologists don’t correctly apply 2007 ACC/AHA guidelines on perioperative cardiac evaluation
BobbieJean Sweitzer, Michael Vigoda, Vicente Behrens, Nikola Miljkovic, Kris Arheart, and Richard Dutton

Abstract 6: Anesthesiology residents do not agree with their training programs on the degree to which the 2007 ACC/AHA guidelines are emphasized
BobbieJean Sweitzer, Michael Vigoda, Vicente Behrens, Nikola Miljkovic, and Kris Arheart

Abstract 7: Prevalence of obstructive sleep apnea in patients presenting for hip or knee replacement surgery
Micah Beachy, DO; Jason Shiffermiller, MD; and Chad Vokoun, MD

Abstract 8: A protocol to triage preoperative assessments to either nurses or nurse practitioners/physician assistants
Anthony Basil, RN; Pamela Pennigar, FNP; David R. Wright, MD; and Ronald P. Olson, MD

Abstract 9: Do ACEIs on the morning of surgery increase risk of intraoperative hypotension?
Steven L. Cohn, MD, and Kalia Skeete, MD

Abstract 10: One-year incidence of postoperative troponin revations in patients undergoing major orthopedic surgery
Michael Urban, MD, PhD; Stephen Wolfe, BS; Niel Sanghevi, BS; and Steven Magid, MD

Abstract 11: A review of preoperative clinic cardiology referrals for adults undergoing intermediate- and low-risk surgery
Susan Calderwood, MD; Jennifer Lee Morse, MS; and Damon R. Michaels, CCRP

Abstract 12: Patterns of preoperative consultation by risk and surgical specialty in a large health care system
Stephan Thilen, MD, MS; Christopher Bryson, MD, MS; Robert Reid, MD, PhD; and Miriam Treggiari, MD, MPH, PhD

Abstract 13: One-year incidence for admission to a critical care unit after major orthopedic surgery
Michael Urban, MD, PhD; Steven Magid, MD; and Michele Mangini, DNP

Abstract 14: Determination of the causes of long patient wait times in a preoperative evaluation clinic
Jean Kwo, MD; Devon Price, BS; Mary Elizabeth Ellbeg, RN; and Retsef Levi, PhD

Abstract 15: Does perioperative statin treatment affect hospital and ICU length of stay rollowing cardiac surgery: A systematic review
Vineet Chopra, MD, FACP, FHM; David Wesorick, MD; and Kim A. Eagle, MD

Abstract 16: Assessment of patient satisfaction of nurse screening vs complete preoperative assessment
Ronald Olson, MD, and Kathy Bock, RN

Abstract 17: Traumatic subdural hematoma: An update on morbidity
Rachel Thompson, MD; Christina Ryan, MD; Nancy Temkin, PhD; Richard Ellenbogen, MD; and Joann G. Elmore, MD, MPH

Abstract 18: Lipid emulsion as a lifesaving treatment for local anesthetic systemic toxicity (LAST)
Deepti Sachdev and Guy Weinberg, MD

Abstract 19: Perioperative ACLS recommendations should be modified for the treatment of local anesthetic toxicity
Adam Haas, MD, and Alexia Beccue, MD

Abstract 20: Preoperative EMR containing smart-set reminders improve accuracy of documentation by nonanesthesia clinicians during preoperative assessments
Angela Edwards, MD; Jill Grant, PA; and Ruth Hyde, MD

Abstract 21: POET: Procedure outcomes evaluation tool
Ahmad AbuSalah, MSc, and Terrence Adam, MD, PhD

Abstract 22: Results of a multidisciplinary preoperative assessment process for high-risk orthopedic patients
Terrence Adam, MD, PhD; Connie Parenti, MD; Terence Gioe, MD; and Karen Ringsred, MD

Abstract 23: Practical algorithm for preoperative evaluation of patients with liver disease
Madalina A. Vlase, PA-C, and Deborah C. Richman, MBChB, FFA(SA)

Abstract 24: Evaluation and management of isolated elevated aPTT
Sheila Hassan, MSN, NP; Patricia Kidik, MSN, NP; Catherine McGowan, MSN, NP; and Angela M. Bader, MD

Abstract 25: A perioperative triage plan for obstructive sleep apnea patients
Christian Altman, MD; R. Michael Boyer, DO; and Peter G. Kallas, MD

Abstract 26: Quantitative evaluation of handoff checklists
Jay Joshi, MD, and David Mayer, MD

Abstract 27: To deflate or not to deflate: Lap-Band® management in subsequent surgeries
Arjun Reddy, MD, and Deborah C. Richman, MBChB, FFA(SA)

Abstract 28: Takotsubo cardiomyopathy and resultant cardiogenic shock after mitral valve repair
Adam Evans, MD, MBA; Daniel B. Sims, MD; Nir Uriel, MD; Ulrich P. Jorde, MD; and Craig R. Smith, MD

Abstract 29: Intravenous vitamin K: Rapid reversal of warfarin and lack of subsequent warfarin resistance
Feras Abdul Khalek, MD; Interdeep Dhaliwal, MD; and Twylla Tassava, MD

Abstract 30: Cervical spine surgery: When not to extubate postoperatively
Carlos Mateo Mijares, MD; Doris Debs, ARNP, MSN-BC; Nicole Martin, MD; and Ronald Lee Samson, MD

Abstract 31: Total occlusion of oral cavity by mandibular sarcoma for resection: To intubate nasally or proceed to an awake tracheostomy?
Carlos Mateo Mijares, MD, and Maria DeLapena, MD

Abstract 32: Perioperative fatal embolic stroke associated with iron deficiency anemia and thrombocytosis
Carlos Mateo Mijares, MD; Nicole Martin, MD; and Ricardo Martinez-Ruiz, MD

Abstract 33: Conservative approach saves the day anesthesia-wise and surgical-wise
Carlos Mateo Mijares, MD; Bradley Shore, MD; Edward Zalkind, CRNA; and Nicole Martin, MD

Abstract 34: Predictors of acute kidney injury in patients undergoing total knee replacement surgery
Vishal Sehgal, MD; Pardeep Bansal, MD; Praveen Reddy, MD; Vishal Sharma, MD; Samuel Lesko, MD; John H. Doherty, MD; Theodore Tomaszewski, MD; Jack Prior, MD; Roger Getts, MD; and Jeremiah Eagan, MD

Abstract 35: Perioperative medical management of the Marfan patient undergoing repeat cardiothoracic surgery
Aashish Shah, MD, and Adam Skrzynski, MD

Index of abstract authors

Summit Director:
Amir K. Jaffer, MD

Contents

Summit Faculty

Summit Program

Abstract 1: Application of 2007 ACC/AHA guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery using decision support tools
BobbieJean Sweitzer, Michael Vigoda, Vicente Behrens, Nikola Miljkovic, and Kris Arheart

Abstract 2: Prevalence of obstructive dleep spnea in patients presenting for hip or knee replacement surgery
Micah Beachy, DO; Jason Shiffermiller, MD; and Chad Vokoun, MD

Abstract 3: A protocol to triage preoperative assessments to either nurses or nurse practitioners/physician assistants
Anthony Basil, RN; Pamela Pennigar, FNP; David R. Wright, MD; and Ronald P. Olson, MD

Abstract 4: Application of 2007 ACC/AHA guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery using decision support tools
BobbieJean Sweitzer, Michael Vigoda, Vicente Behrens, Nikola Miljkovic, and Kris Arheart

Abstract 5: Most anesthesiologists don’t correctly apply 2007 ACC/AHA guidelines on perioperative cardiac evaluation
BobbieJean Sweitzer, Michael Vigoda, Vicente Behrens, Nikola Miljkovic, Kris Arheart, and Richard Dutton

Abstract 6: Anesthesiology residents do not agree with their training programs on the degree to which the 2007 ACC/AHA guidelines are emphasized
BobbieJean Sweitzer, Michael Vigoda, Vicente Behrens, Nikola Miljkovic, and Kris Arheart

Abstract 7: Prevalence of obstructive sleep apnea in patients presenting for hip or knee replacement surgery
Micah Beachy, DO; Jason Shiffermiller, MD; and Chad Vokoun, MD

Abstract 8: A protocol to triage preoperative assessments to either nurses or nurse practitioners/physician assistants
Anthony Basil, RN; Pamela Pennigar, FNP; David R. Wright, MD; and Ronald P. Olson, MD

Abstract 9: Do ACEIs on the morning of surgery increase risk of intraoperative hypotension?
Steven L. Cohn, MD, and Kalia Skeete, MD

Abstract 10: One-year incidence of postoperative troponin revations in patients undergoing major orthopedic surgery
Michael Urban, MD, PhD; Stephen Wolfe, BS; Niel Sanghevi, BS; and Steven Magid, MD

Abstract 11: A review of preoperative clinic cardiology referrals for adults undergoing intermediate- and low-risk surgery
Susan Calderwood, MD; Jennifer Lee Morse, MS; and Damon R. Michaels, CCRP

Abstract 12: Patterns of preoperative consultation by risk and surgical specialty in a large health care system
Stephan Thilen, MD, MS; Christopher Bryson, MD, MS; Robert Reid, MD, PhD; and Miriam Treggiari, MD, MPH, PhD

Abstract 13: One-year incidence for admission to a critical care unit after major orthopedic surgery
Michael Urban, MD, PhD; Steven Magid, MD; and Michele Mangini, DNP

Abstract 14: Determination of the causes of long patient wait times in a preoperative evaluation clinic
Jean Kwo, MD; Devon Price, BS; Mary Elizabeth Ellbeg, RN; and Retsef Levi, PhD

Abstract 15: Does perioperative statin treatment affect hospital and ICU length of stay rollowing cardiac surgery: A systematic review
Vineet Chopra, MD, FACP, FHM; David Wesorick, MD; and Kim A. Eagle, MD

Abstract 16: Assessment of patient satisfaction of nurse screening vs complete preoperative assessment
Ronald Olson, MD, and Kathy Bock, RN

Abstract 17: Traumatic subdural hematoma: An update on morbidity
Rachel Thompson, MD; Christina Ryan, MD; Nancy Temkin, PhD; Richard Ellenbogen, MD; and Joann G. Elmore, MD, MPH

Abstract 18: Lipid emulsion as a lifesaving treatment for local anesthetic systemic toxicity (LAST)
Deepti Sachdev and Guy Weinberg, MD

Abstract 19: Perioperative ACLS recommendations should be modified for the treatment of local anesthetic toxicity
Adam Haas, MD, and Alexia Beccue, MD

Abstract 20: Preoperative EMR containing smart-set reminders improve accuracy of documentation by nonanesthesia clinicians during preoperative assessments
Angela Edwards, MD; Jill Grant, PA; and Ruth Hyde, MD

Abstract 21: POET: Procedure outcomes evaluation tool
Ahmad AbuSalah, MSc, and Terrence Adam, MD, PhD

Abstract 22: Results of a multidisciplinary preoperative assessment process for high-risk orthopedic patients
Terrence Adam, MD, PhD; Connie Parenti, MD; Terence Gioe, MD; and Karen Ringsred, MD

Abstract 23: Practical algorithm for preoperative evaluation of patients with liver disease
Madalina A. Vlase, PA-C, and Deborah C. Richman, MBChB, FFA(SA)

Abstract 24: Evaluation and management of isolated elevated aPTT
Sheila Hassan, MSN, NP; Patricia Kidik, MSN, NP; Catherine McGowan, MSN, NP; and Angela M. Bader, MD

Abstract 25: A perioperative triage plan for obstructive sleep apnea patients
Christian Altman, MD; R. Michael Boyer, DO; and Peter G. Kallas, MD

Abstract 26: Quantitative evaluation of handoff checklists
Jay Joshi, MD, and David Mayer, MD

Abstract 27: To deflate or not to deflate: Lap-Band® management in subsequent surgeries
Arjun Reddy, MD, and Deborah C. Richman, MBChB, FFA(SA)

Abstract 28: Takotsubo cardiomyopathy and resultant cardiogenic shock after mitral valve repair
Adam Evans, MD, MBA; Daniel B. Sims, MD; Nir Uriel, MD; Ulrich P. Jorde, MD; and Craig R. Smith, MD

Abstract 29: Intravenous vitamin K: Rapid reversal of warfarin and lack of subsequent warfarin resistance
Feras Abdul Khalek, MD; Interdeep Dhaliwal, MD; and Twylla Tassava, MD

Abstract 30: Cervical spine surgery: When not to extubate postoperatively
Carlos Mateo Mijares, MD; Doris Debs, ARNP, MSN-BC; Nicole Martin, MD; and Ronald Lee Samson, MD

Abstract 31: Total occlusion of oral cavity by mandibular sarcoma for resection: To intubate nasally or proceed to an awake tracheostomy?
Carlos Mateo Mijares, MD, and Maria DeLapena, MD

Abstract 32: Perioperative fatal embolic stroke associated with iron deficiency anemia and thrombocytosis
Carlos Mateo Mijares, MD; Nicole Martin, MD; and Ricardo Martinez-Ruiz, MD

Abstract 33: Conservative approach saves the day anesthesia-wise and surgical-wise
Carlos Mateo Mijares, MD; Bradley Shore, MD; Edward Zalkind, CRNA; and Nicole Martin, MD

Abstract 34: Predictors of acute kidney injury in patients undergoing total knee replacement surgery
Vishal Sehgal, MD; Pardeep Bansal, MD; Praveen Reddy, MD; Vishal Sharma, MD; Samuel Lesko, MD; John H. Doherty, MD; Theodore Tomaszewski, MD; Jack Prior, MD; Roger Getts, MD; and Jeremiah Eagan, MD

Abstract 35: Perioperative medical management of the Marfan patient undergoing repeat cardiothoracic surgery
Aashish Shah, MD, and Adam Skrzynski, MD

Index of abstract authors

Malignant bowel obstruction occurs in 5% to 51% of women with ovarian cancer and in 10% to 28% of patients with gastrointestinal cancer, predominantly in the advanced stages.¹ Median survival after its onset ranges from 30 to 90 days.^2–5

Its symptoms are challenging to manage, since nausea, vomiting, colic, and abdominal pain, which are common, cause significant physical distress and demoralization. The decision whether to correct it with surgery requires an individualized approach and a clear understanding of the goals of care and expected survival in the individual patient.

This review focuses on the management of inoperable malignant bowel obstruction and includes discussion of hydration, nutrition, and endoscopic palliative options.

WHAT ARE THE DIFFERENT TYPES OF OBSTRUCTION?

Bowel obstruction may be mechanical or functional, partial or complete, and may occur at one or at many sites. Tumors can impair bowel function in several ways^6–8:

• Intraluminal tumors can occlude the lumen or act as a point of intussusception.
• Intramural tumors can extend to the mucosa and obstruct the lumen or impair peristalsis.
• Mesenteric and omental masses or malignant adhesions can kink or angulate the bowel, creating an extramural obstruction.
• Tumors that infiltrate into the mesentery, bowel muscle, or the enteric or celiac plexus can cause dysmotility.

Cholangiocarcinoma, pancreatic carcinoma, and gallbladder carcinoma are the most common tumors causing duodenal obstruction.⁹ Distal obstruction is caused mainly by colon and ovarian cancer.

Obstruction can be due to treatment

In a minority of patients, obstruction is unrelated to the cancer and is instead due to adhesions arising from surgery, radiation therapy (causing enteritis and strictures), desmoplastic reactions to intraperitoneal chemotherapy, torsion, or internal hernias.^10–12

In rare cases, a patient has intestinal pseudo-obstruction from paraneoplastic destruction of enteric neurons, or severe ileus from anticholinergic or sympathomimetic drugs, as seen with acute colonic pseudo-obstruction (Ogilvie syndrome).¹³

Physiologic reactions to obstruction

Malignant bowel obstruction stimulates gastric, biliary, pancreatic, and intestinal secretions, decreases intraluminal sodium and water reabsorption, and increases mucosal sodium and water secretion.^6,14 In response to the obstruction, peristalsis increases, and prostaglandin, vasoactive intestinal peptide, and nociceptive mediators are released. Vasoactive intestinal polypeptide perpetuates a cycle of secretion, distention, and contraction that leads to intestinal hyperemia, bowel edema, and accumulation of fluid in the lumen.^8,10,11,15

Signs and symptoms depend on the site

The site of obstruction determines the signs and symptoms patients experience.^7,14 Obstructions high in the gastrointestinal tract are associated with greater symptoms but fewer signs than colonic obstructions.¹ Patients with proximal small-bowel obstruction have more severe nausea and a greater number of episodes of emesis, but they have relatively normal plain radiographs of the abdomen, which do not have the characteristic air-fluid levels commonly seen with distal small-bowel obstruction.

Most malignant obstructions remain partial, but increasing abdominal distention, worsening nausea, vomiting, abdominal pain, and obstipation over 1 to 2 weeks¹ suggest progression to complete obstruction.

IMAGING TESTS FOR MALIGNANT BOWEL OBSTRUCTION

What is the value of plain radiography?

Despite these limitations, plain radiography is useful in assessing constipation and its severity as a potential cause of symptoms, and thus it remains an important initial imaging study in almost all patients with suspected malignant bowel obstruction.^17,18 It is also used to assess response to treatment.

When do you need contrast radiographs?

Contrast radiography (barium swallow or barium or Gastrograffin enema) is helpful in patients with symptoms of dysmotility from suspected bowel obstruction. It defines the site or sites of obstruction and the extent of the obstruction with a fair degree of accuracy.^7,19 Single-contrast studies, if positive, exclude opioid-induced bowel dysfunction or pseudo-obstruction in 83% of patients, with a sensitivity and specificity of 96% and 98%, respectively.^8,20 Small-bowel follow-through with barium is more appropriate for low-grade obstructions or for symptomatic patients with a normal kidney, ureter, bladder radiograph.¹⁹

However, contrast radiography is limited by the patient’s ability to swallow barium or water-soluble contrast agents, and it can worsen nausea or vomiting.^17,18 Also, barium is not absorbed systemically and may interfere with subsequent radiologic studies. Large volumes of contrast agents increase the risk of aspiration pneumonia in patients with poorly controlled nausea and can lead to severe impaction proximal to the obstructed site.⁸

Enteroclysis, ie, injecting radiographic contrast into the bowel via a nasoduodenal tube, has some advantages over the barium swallow technique for detecting partial small-bowel obstruction, since it bypasses the stomach and allows for therapeutic decompression as well as direct visualization of the area of concern.^17,18 Enteroclysis radiography objectively gauges severity of intestinal obstruction and bowel wall distensibility, which is an advantage over other imaging studies. Its sensitivity is 100% and specificity 88% in experienced hands.¹⁷ Enteroclysis studies also detect nonobstructing intraluminal tumors when computed tomography (CT) is not diagnostic.^17,18,21

The drawbacks to enteroclysis are that it is technically difficult to perform and that few radiologists are trained in it.

When is CT useful?

CT is the primary imaging study for patients with obstructive symptoms and a history of abdominal malignancy or a palpable abdominal mass^17,20,22,23 (Figure 1). It has a specificity of 100% and a sensitivity of 94%. It plays a major role in decision-making regarding surgery, endoscopy, or palliative interventions,^7,19 as it locates the obstruction and differentiates benign from malignant causes with a fair degree of precision.²²

CT findings in malignant bowel obstruction may include:

• A mass at the site of obstruction or within the original surgical field
• Lymphadenopathy
• Abrupt transitions in luminal diameter or irregular thickening of the bowel wall at the site or sites of obstruction.⁷

SURGERY: A DIFFICULT DECISION

Is the patient fit for surgery?

Surgery for malignant bowel obstruction should not be done in patients who have advanced malignancies with bulky intra-abdominal metastases or cancer that has spread outside the abdominal cavity without taking into account treatment options for the cancer, the patient’s nutritional status, and the goals of care.

The role of abdominal surgery (debulking, resection, or bypass) in advanced cancer remains unclear and controversial.²⁴ From 42% to 80% of patients report that symptoms improve after surgery, but recurrent obstruction occurs in 10% to 50%.¹⁰ Even in patients with low tumor bulk and good nutritional status, 30-day mortality rates range from 5% to 40%, and complication rates range from 9% to 90%.^{3,4,6,7,10,14}

Outcomes after surgery depend on patient selection criteria perhaps as much as on the surgeon’s experience and skill. Patients with more advanced cancer who have had multiple surgical procedures and those with cancer that does not respond to chemotherapy and radiation present the greatest challenge to surgeons.²³

What is the benefit of surgery?

Reports of palliative surgery have included information about 60-day survival rates after the operation, but a number of factors may be more meaningful in this context, such as postoperative symptoms, the patient’s overall wellbeing, how the original symptoms respond to the surgery, complications, and length of hospitalization.¹⁴ The paucity of published, validated, patient-related outcome data on which to gauge the value of surgery and the lack of a standard definition of “benefit” further confuse the objective determination of whether these patients benefit from surgery.

In a cohort with advanced ovarian cancer and bowel obstruction, surgery was detrimental to survival and quality of life for all subgroups, and most patients died in the hospital.⁶

The risk of surgery for malignant bowel obstruction is presumably higher than for abdominal surgery for other indications, since many of the patients are debilitated from their cancer and chemotherapy, and many are malnourished.²³ Even when taking into account a potential selection bias in favor of surgery, several studies have reported no significant difference in 30-day mortality rates or median survival between operative and nonoperative groups.^2,12 Neither the type of obstruction nor the extent of the surgery influenced outcomes. Surgical outcomes are best in patients with a benign cause of obstruction; little benefit is seen in operating on those with abdominal carcinomatosis.¹²

Nevertheless, surgery is beneficial in a select few. For patients with a good performance status, slowly progressive cancer, and an expected survival of more than 6 months, surgical bypass or resection is preferred.^7,12,25 The challenge is to identify these surgical candidates, taking into account prognostic factors such as nutritional status, tumor burden, performance status, presence of ascites, advanced age, extensive prior chemotherapy or radiotherapy, and diffuse carcinomatosis.^{3,10,12,20,23}

Is surgery consistent with the goals of care?

Crucial to decision-making are the goals of care. Since palliative surgery carries a low level of evidence for benefit in terms of quality of life and survival, time should be set aside to thoroughly review the patient’s medical condition, to explore options, and to clarify expectations and goals of care.^3,10 Family members should be invited to be present during these discussions and to be involved in the decision-making process.

WHAT IS THE BENEFIT OF GASTRIC OR COLONIC STENTING?

Endoscopic procedures are alternatives to surgery and offer a palliative option in malignant bowel obstruction. Endoscopic procedures are associated with a shorter hospital stay and quicker recovery than after laparotomy.^9,26–30 In certain situations, stenting serves as a bridge to surgery, allowing time to mitigate comorbid conditions, to enhance nutrition, and to complete staging, while relieving symptoms.^{27–29,31,32} Definitive surgery can be done as a single-stage procedure without a diverting enterostomy.

Self-expanding metal stents for gastric outlet, small-bowel, and colonic obstructions are an option in patients who have incurable metastatic disease who are unfit for surgery, in patients with a single point of obstruction or locally extensive disease, or in patients who do not want to undergo laparotomy.^28–30

Technical and clinical success rates for colorectal stenting are high (88% to 93%).^26,27 Stenting is more successful for left-sided colonic obstructions than for proximal colonic obstructions. Even for patients with extracolonic malignancies such as ovarian cancer, the technical success rate of colorectal stenting is 87%.²⁶ However, patients with unrecognized peritoneal carcinomatosis or multifocal bowel obstruction are less likely to have symptomatic relief even after successful stenting.^6,9

Absolute contraindications to stenting are colonic or tumor perforation with peritonitis. A relative contraindication is a rectal tumor within 2 cm of the anal margin. Stenting in this circumstance leads to tenesmus and incontinence.³³

Complications of stenting

Death rates during colorectal stent insertion are less than 1%. The hospital stay and incidence of complications are significantly less than with surgery.^26,30

Stent migration occurs in 10% of cases and is asymptomatic, but half of patients with this complication require a repeat intervention. The risk of migration is greater if chemotherapy or radiation therapy succeeds in shrinking the tumor.

Bleeding occurs in 5% of cases, usually from the underlying tumor.

Perforation occurs in 4%, but the rate increases to 10% with the use of dilatation before stent placement.

The rate of recurrent obstruction from tumor ingrowth, overgrowth, or fecal impaction is 10%.^9,26,29 Recurrent obstruction may be treated with additional stents inserted within the original stent.⁹

GASTRIC OUTLET OBSTRUCTION: SURGERY VS STENTING

Gastrojejunostomy has in the past been the treatment of choice for gastric outlet obstruction. Certainly, patients with slow-growing tumors and an expected survival of greater than 60 days may be considered for this bypass procedure; those with a short tumor length, a single site of obstruction (preferably in the pylorus or proximal duodenum), a good performance status, and a life expectancy greater than 30 days are good candidates.⁷ Nevertheless, for patients with advanced cancer and poor performance status, gastroenterostomy carries a significant risk of morbidity and death.²⁸

Endoscopic stenting of gastric outlet obstruction has a greater success rate, a shorter time to oral intake, a lower morbidity rate, a lower incidence of delayed gastric emptying, and a shorter hospital stay compared with gastroenterostomy.^28,29 Technical success rates of stenting are 90%, and 75% of patients have resolution of nausea and vomiting.⁷ Stenting is generally not possible if the obstruction occurs beyond the ligament of Treitz.

Patients who are expected to survive less than 1 month or who have rapidly progressive disease, overt ascites, carcinomatosis, or multiple sites of obstruction should be managed with percutaneous, endoscopically placed gastrostomy tubes.⁷

Late complications of stenting for gastric outlet obstruction are occlusion with food or ingrowth of tumor through or around the wire mesh.⁷ This may require laser therapy or placement of a second stent, or both.

DRUG THERAPY

Medical therapy can palliate symptoms of malignant bowel obstruction for most patients.³⁴ Recommendations have been published by the Working Group of the European Association for Palliative Care.²⁴ Symptom management is focused on pain, nausea, and vomiting.

Which drugs can I use for abdominal pain?

Patients experience two types of abdominal pain: continuous and colic. Each type of pain requires different treatment approaches and classes of drugs.

Potent opioids such as morphine, hydromorphone (Dilaudid), and fentanyl (Fentora) are used to relieve continuous abdominal pain.⁷ The dose is titrated for adequate relief. Subcutaneous, intravenous, sublingual, and transdermal routes can be used if nausea and vomiting prevent oral administration.

However, opioids can aggravate colic by stimulating circular smooth muscle, leading to segmental contractions. Opioid-sparing adjuvant drugs such as ketorolac (Toradol) may improve colic and continuous pain and prevent a partial obstruction from becoming a complete obstruction by sparing opioid doses.³⁵

Colic may persist or worsen with the use of opioids. Drugs that reduce colic include the scopolamine drugs hyoscine butylbromide and hyoscine hydrobromide, glycopyrrolate (Robinul), and octreotide (Sandostatin).^7,34–37

Which drugs are appropriate for reducing nausea and vomiting?

Phenothiazines reduce nausea and control vomiting. Chlorpromazine (Thorazine), prochlorperazine (Compro, Compazine), and promethazine (Phenergan) have all been reported to treat nausea successfully.^35,37

Haloperidol (Haldol), a butyrophenone selective dopamine D2-receptor antagonist, has negligible anticholinergic activity. At low doses it produces less sedation than phenothiazines and is an ideal agent for patients with nausea and delirium.³⁵ Doses range from 5 to 15 mg/day, given in divided doses or as intermittent or continuous intravenous infusions.

Anticholinergics, with or without somatostatin analogues, reduce gastrointestinal secretions, fluid accumulation, and vomiting. Anticholinergics bind to muscarinic receptors on enteric neurons in the myenteric and the submucosal plexus. Dosages:

• Hyoscine butylbromide 40 to 120 mg/day.
• Hyoscine hydrobromide 0.2 to 0.9 mg/day.^7,34

Glycopyrrolate, a quaternary ammonium anticholinergic, has minimal central nervous system penetration and is less likely to cause delirium or cardiac side effects compared with tertiary amine anticholinergics such as atropine and scopolamine.³⁸ The recommended dose is 0.1 to 0.2 mg subcutaneously or intravenously three to four times daily.

Octreotide, an analogue of somatostatin, blocks the release of vasoactive intestinal polypeptide, which is increased in malignant bowel obstruction.^14,15 It reduces the excretion of water, sodium, and chloride into the bowel lumen and increases the absorption of electrolytes and water. It also inhibits pancreatic enzyme secretion and splanchnic blood flow. The result of all these effects is reduced luminal content, reduced motility, reduced vascular congestion of the bowel wall, and, in certain circumstances, reduced ascites.³⁹

In small randomized trials, octreotide was more successful than anticholinergics at improving nausea, vomiting, and colic in patients requiring a nasogastric tube and in those whose symptoms were refractory to standard medical treatment.^5,34,40–43 A recent case report found octreotide helpful in resolving symptoms of partial bowel obstruction that were unresponsive to standard measures.⁴⁴

Octreotide is well tolerated and reduces the time patients require a nasogastric tube without significantly worsening xerostomia. High cost limits its use in American hospice care due to the Medicare capitated system of reimbursement for drugs and services, and as a result it is a second-tier drug despite evidence of its efficacy.

Octreotide doses are 100 to 200 mg every 8 hours.

Metoclopramide (Reglan), a dopaminergic antagonist, a 5HT4 receptor agonist, and a 5HT3 receptor blocker at doses greater than 120 mg/day, combines the action of a phenothiazine, which blocks D2 receptors in the central chemoreceptor trigger zone, with promotility actions through serotonin receptors (5HT4).^35,37

Metoclopramide should not be used with anticholinergics or in patients with colic or complete obstruction.^35,45 In some centers it is the first-line drug for functional or partial bowel obstruction.⁷ Dosages range from 40 to 240 mg/day.

Olanzapine (Zyprexa), an atypical antipsychotic, blocks multiple neurotransmitter receptors (D2, H1, Ach, 5HT3) responsible for initiating emesis. It is an option in patients whose nausea and vomiting fail to respond to standard antiemetics.⁴⁶ Dosages range from 2.5 to 20 mg/day.

Dissolvable tablets are given sublingually, which makes olanzapine a versatile antiemetic in cases of intractable nausea. Our unpublished experience is that the sublingual route reduces nausea associated with malignant bowel obstruction and obviates the need for subcutaneous injections or intravenous antiemetic infusions.

Corticosteroids. Although how corticosteroids relieve malignant bowel obstruction is unknown, they are presumed to act centrally.^37,45 In addition, they reduce peritumoral edema and luminal salt and water, and they also have antiemetic and analgesic properties.

Evidence from a meta-analysis found that 6 to 16 mg of parenteral dexamethasone per day reduced symptoms and improved bowel function in 60% of patients but did not change the prognosis.¹¹

A trial of 4 or 5 days is adequate to determine response. If there is no response, the corticosteroid should be rapidly tapered. Side effects are minimal when corticosteroids are used short-term.

Combination therapy. Only rarely does a single drug resolve symptoms of malignant bowel obstruction. Antiemetics, analgesics, corticosteroids, antisecretory anticholinergics, and octreotide are often required in combination to achieve acceptable symptom relief.^3,5,7,47

In a small prospective case series, the combination of metoclopramide 60 mg/day, octreotide 0.3 mg/day, and dexamethasone 12 mg/day with a single bolus of amidotrizoic acid (a contrast agent) improved intestinal transit within 1 to 5 days and resolved vomiting within 24 hours.⁴⁵

Compatibility and the route of administration of medications are key considerations when choosing drug combinations.

WHEN TO CONSIDER A VENTING GASTROSTOMY

Patients with a poor performance status, rapidly progressive disease, peritoneal carcinomatosis, a life expectancy of less than 30 days, or multiple levels of obstruction benefit from placement of a percutaneous endoscopic gastrostomy tube (ie, a venting gastrostomy) rather than surgery if symptoms do not respond to drug therapy.^7,48 There is compelling evidence that this procedure relieves nausea and vomiting in 80% to 90% of patients and restores some level of oral intake in many.^5,6,48,49 A venting gastrostomy tube can be placed during surgical exploration, percutaneously with fluoroscopy, or endoscopically.⁹

There are no absolute contraindications to gastrostomy tube placement. It is feasible even in patients with tumors encasing the stomach, diffuse carcinomatosis, and ascites.⁴⁸ However, massive ascites, previous upper abdominal surgery, or a large mass attached to the abdominal wall make tube placement difficult.

Complications are often local. Patients experience transient abdominal wall pain after the procedure. Dislodgement, bleeding, catheter migration, peritonitis, and necrotizing fasciitis are early complications. Others include skin excoriation from leakage of gastric contents, leakage of ascitic fluid from the site, and obstruction or dislodgement of the tube.^48,49

Patients can be discharged from the hospital soon after the tube is placed, usually with fewer medications than for patients who undergo surgery.⁴⁸ This is particularly important for patients with a short expected survival. Some patients at home benefit from hydration (less than 2 L/day) via an existing central venous port or peripherally inserted central catheter, or by hypodermoclysis.

WHEN IS A NASOGASTRIC TUBE APPROPRIATE?

Some patients with malignant bowel obstruction require a nasogastric tube early in their hospital course.¹² Unfortunately, nasogastric tubes, if left in place, cause nose and throat pain, sinusitis, abscess formation, erosion of nasal cartilage, aspiration, esophageal erosion, pharyngitis, and social isolation.^5,6

Nasogastric tubes should be a temporizing measure to vent gastrointestinal secretions, reduce abdominal distension, and improve nausea and vomiting while a decision about surgery is being made.^13,24 If surgery is not feasible, one can avoid the long-term complications and discomfort of a nasogastric tube via medical management and earlier evaluation for venting gastrostomy in those with symptoms that respond poorly to optimal medical management.⁴⁹

WHICH PATIENTS BENEFIT FROM TOTAL PARENTERAL NUTRITION?

The use of total parenteral nutrition in patients with incurable malignancies is controversial. Enteral and parenteral feeding can increase muscle mass and improve functional status and quality of life in a subset of patients who are not suffering from cancer-related cachexia.^2,50,51 However, for those whose weight loss and malnutrition are consequences of tumor-mediated cachexia, as demonstrated by anorexia and an elevated C-reactive protein level, parenteral nutrition is unlikely to improve the outcome.⁵¹ For most terminally ill patients, retrospective studies have failed to show that parenteral nutrition improves overall survival, performance status, or quality of life.^2,48,50–54

Total parenteral nutrition poses risks: it is invasive and requires central venous access, which predisposes to infection; it requires frequent monitoring of hydration and electrolytes; and it predisposes to thrombosis, diarrhea, hyperglycemia, and liver failure.^50–56

Total parenteral nutrition may be justified in patients with minimal tumor burden who are candidates for definitive surgery, or in those with a good performance status early in the disease course who have not had chemotherapy or whose cancer responds to chemotherapy.^2,50–56

The American College of Physicians discourages the routine use of parenteral nutrition in those with advanced cancer who are undergoing palliative chemotherapy, since few patients benefit and many experience side effects.⁵³

Total parenteral nutrition is much like a medical intervention in that it should be offered or continued only if it provides benefit. Conversations at the time that it is begun must include adverse effects that will lead to its discontinuation, and criteria for response. In certain situations, a limited trial of parenteral nutrition may be considered for patients with an uncertain prognosis or for those who have potentially reversible conditions that limit oral intake.⁵¹ In such cases, there should be a clear understanding between patient and physician that parenteral nutrition will be discontinued if it fails to show benefit.⁵³

ADDITIONAL CONCERNS OF PATIENTS AND FAMILIES

‘Will I starve to death?’

Starvation is a fear echoed by patients and families. Ethical discourse on the continuation of nutrition and hydration for the terminally ill has been polarizing.^57–60 Withdrawal of nutrition can be perceived as euthanasia.

Advanced cancer patients in general do not experience hunger, and those who do require only small amounts of food for satiation.⁶¹ In one report, most patients died of their advanced cancer and not from starvation.⁵² Artificial hydration and nutrition will thus not influence survival and can even be a burden without benefit in the imminently dying.⁶⁰ These patients should be encouraged to take food orally for pleasure, as long as it is tolerated, without consideration of end points such as weight gain, body mass index, or albumin levels.

Complaints of thirst and dryness of the mouth are relieved with mouth care, ice chips, lubrication to the lips, and sips of fluid, rather than by parenteral nutrition.⁵⁹ Patients with a terminal illness experience relief from thirst with minimal intake. The symptom of thirst may be relieved without hydration.^34,61 Adequate hydration requires smaller fluid volumes due to decreased body weight, decreased renal clearance of free water, and decreased insensible water losses from reduced physical activity.⁵⁸

‘Can we continue intravenous hydration so he won’t die of thirst?’

Overzealous intravenous hydration may worsen the symptoms of malignant bowel obstruction. Overhydration can increase secretions in the gut lumen and worsen the secretion-distention-contraction cycle, leading to greater abdominal pain and to nausea and vomiting.⁷ There is a greater risk of fluid overload in these patients, since they have edema and excessive interstitial fluid. Most have a low serum albumin level, which results in movement of fluid from intravascular to interstitial spaces due to reduced colloid osmotic pressure. In these instances, overzealous hydration can lead to respiratory insufficiency and worsening edema.

In spite of numerous discussions in the medical literature of the benefits and burdens of continual hydration, there is no consensus or guideline. When a patient has limited oral intake, the decision to hydrate should be individualized, with careful assessment of the risks and benefits and in accordance with the patient’s or family’s wishes.^57,58

Discharging patients with inoperable malignant bowel obstruction requires careful planning. Patients and family members need to be educated on the use of around-the-clock medications and symptom-targeted, as-needed drugs. Days before discharge, questions about diet need to be clarified. Education about total parenteral nutrition and gastrostomy tube care should be completed before discharge from the hospital.

Drug management should be simplified, or compatible medications should be combined into a single infusion. For example, morphine, glycopyrrolate, and haloperidol or metoclopramide are chemically compatible in standard intravenous solutions and can be combined.

Families feel less anxious about the foreseen and the possible unforeseen course of the illness if they can talk with hospice workers early on. This early involvement also facilitates the transition to home hospice care.

SUMMARY OF IMPORTANT POINTS

• Patients with malignant bowel obstruction need a highly individualized approach, tailored to their medical condition, the prognosis, and the goals of care.
• Surgery should not be routinely undertaken; less-invasive approaches such as gastric or colonic stenting should be considered first.
• Combinations of analgesics, antisecretory drugs, and antiemetics can provide acceptable symptom relief in the inoperable patient.
• A venting gastrostomy should be considered if drug therapy fails to reduce nausea and vomiting to an acceptable level.
• A nasogastric tube should be used only as a temporizing measure, until symptoms are controlled medically or a venting gastrostomy is placed.
• Total parenteral nutrition is of benefit only in patients with intermediate life expectancy who may otherwise die of starvation rather than from the cancer itself.

Malignant bowel obstruction occurs in 5% to 51% of women with ovarian cancer and in 10% to 28% of patients with gastrointestinal cancer, predominantly in the advanced stages.¹ Median survival after its onset ranges from 30 to 90 days.^2–5

Its symptoms are challenging to manage, since nausea, vomiting, colic, and abdominal pain, which are common, cause significant physical distress and demoralization. The decision whether to correct it with surgery requires an individualized approach and a clear understanding of the goals of care and expected survival in the individual patient.

This review focuses on the management of inoperable malignant bowel obstruction and includes discussion of hydration, nutrition, and endoscopic palliative options.

WHAT ARE THE DIFFERENT TYPES OF OBSTRUCTION?

Bowel obstruction may be mechanical or functional, partial or complete, and may occur at one or at many sites. Tumors can impair bowel function in several ways^6–8:

• Intraluminal tumors can occlude the lumen or act as a point of intussusception.
• Intramural tumors can extend to the mucosa and obstruct the lumen or impair peristalsis.
• Mesenteric and omental masses or malignant adhesions can kink or angulate the bowel, creating an extramural obstruction.
• Tumors that infiltrate into the mesentery, bowel muscle, or the enteric or celiac plexus can cause dysmotility.

Cholangiocarcinoma, pancreatic carcinoma, and gallbladder carcinoma are the most common tumors causing duodenal obstruction.⁹ Distal obstruction is caused mainly by colon and ovarian cancer.

Obstruction can be due to treatment

In a minority of patients, obstruction is unrelated to the cancer and is instead due to adhesions arising from surgery, radiation therapy (causing enteritis and strictures), desmoplastic reactions to intraperitoneal chemotherapy, torsion, or internal hernias.^10–12

In rare cases, a patient has intestinal pseudo-obstruction from paraneoplastic destruction of enteric neurons, or severe ileus from anticholinergic or sympathomimetic drugs, as seen with acute colonic pseudo-obstruction (Ogilvie syndrome).¹³

Physiologic reactions to obstruction

Malignant bowel obstruction stimulates gastric, biliary, pancreatic, and intestinal secretions, decreases intraluminal sodium and water reabsorption, and increases mucosal sodium and water secretion.^6,14 In response to the obstruction, peristalsis increases, and prostaglandin, vasoactive intestinal peptide, and nociceptive mediators are released. Vasoactive intestinal polypeptide perpetuates a cycle of secretion, distention, and contraction that leads to intestinal hyperemia, bowel edema, and accumulation of fluid in the lumen.^8,10,11,15

Signs and symptoms depend on the site

The site of obstruction determines the signs and symptoms patients experience.^7,14 Obstructions high in the gastrointestinal tract are associated with greater symptoms but fewer signs than colonic obstructions.¹ Patients with proximal small-bowel obstruction have more severe nausea and a greater number of episodes of emesis, but they have relatively normal plain radiographs of the abdomen, which do not have the characteristic air-fluid levels commonly seen with distal small-bowel obstruction.

Most malignant obstructions remain partial, but increasing abdominal distention, worsening nausea, vomiting, abdominal pain, and obstipation over 1 to 2 weeks¹ suggest progression to complete obstruction.

IMAGING TESTS FOR MALIGNANT BOWEL OBSTRUCTION

What is the value of plain radiography?

Despite these limitations, plain radiography is useful in assessing constipation and its severity as a potential cause of symptoms, and thus it remains an important initial imaging study in almost all patients with suspected malignant bowel obstruction.^17,18 It is also used to assess response to treatment.

When do you need contrast radiographs?

Contrast radiography (barium swallow or barium or Gastrograffin enema) is helpful in patients with symptoms of dysmotility from suspected bowel obstruction. It defines the site or sites of obstruction and the extent of the obstruction with a fair degree of accuracy.^7,19 Single-contrast studies, if positive, exclude opioid-induced bowel dysfunction or pseudo-obstruction in 83% of patients, with a sensitivity and specificity of 96% and 98%, respectively.^8,20 Small-bowel follow-through with barium is more appropriate for low-grade obstructions or for symptomatic patients with a normal kidney, ureter, bladder radiograph.¹⁹

However, contrast radiography is limited by the patient’s ability to swallow barium or water-soluble contrast agents, and it can worsen nausea or vomiting.^17,18 Also, barium is not absorbed systemically and may interfere with subsequent radiologic studies. Large volumes of contrast agents increase the risk of aspiration pneumonia in patients with poorly controlled nausea and can lead to severe impaction proximal to the obstructed site.⁸

Enteroclysis, ie, injecting radiographic contrast into the bowel via a nasoduodenal tube, has some advantages over the barium swallow technique for detecting partial small-bowel obstruction, since it bypasses the stomach and allows for therapeutic decompression as well as direct visualization of the area of concern.^17,18 Enteroclysis radiography objectively gauges severity of intestinal obstruction and bowel wall distensibility, which is an advantage over other imaging studies. Its sensitivity is 100% and specificity 88% in experienced hands.¹⁷ Enteroclysis studies also detect nonobstructing intraluminal tumors when computed tomography (CT) is not diagnostic.^17,18,21

The drawbacks to enteroclysis are that it is technically difficult to perform and that few radiologists are trained in it.

When is CT useful?

CT is the primary imaging study for patients with obstructive symptoms and a history of abdominal malignancy or a palpable abdominal mass^17,20,22,23 (Figure 1). It has a specificity of 100% and a sensitivity of 94%. It plays a major role in decision-making regarding surgery, endoscopy, or palliative interventions,^7,19 as it locates the obstruction and differentiates benign from malignant causes with a fair degree of precision.²²

CT findings in malignant bowel obstruction may include:

• A mass at the site of obstruction or within the original surgical field
• Lymphadenopathy
• Abrupt transitions in luminal diameter or irregular thickening of the bowel wall at the site or sites of obstruction.⁷

SURGERY: A DIFFICULT DECISION

Is the patient fit for surgery?

Surgery for malignant bowel obstruction should not be done in patients who have advanced malignancies with bulky intra-abdominal metastases or cancer that has spread outside the abdominal cavity without taking into account treatment options for the cancer, the patient’s nutritional status, and the goals of care.

The role of abdominal surgery (debulking, resection, or bypass) in advanced cancer remains unclear and controversial.²⁴ From 42% to 80% of patients report that symptoms improve after surgery, but recurrent obstruction occurs in 10% to 50%.¹⁰ Even in patients with low tumor bulk and good nutritional status, 30-day mortality rates range from 5% to 40%, and complication rates range from 9% to 90%.^{3,4,6,7,10,14}

Outcomes after surgery depend on patient selection criteria perhaps as much as on the surgeon’s experience and skill. Patients with more advanced cancer who have had multiple surgical procedures and those with cancer that does not respond to chemotherapy and radiation present the greatest challenge to surgeons.²³

What is the benefit of surgery?

Reports of palliative surgery have included information about 60-day survival rates after the operation, but a number of factors may be more meaningful in this context, such as postoperative symptoms, the patient’s overall wellbeing, how the original symptoms respond to the surgery, complications, and length of hospitalization.¹⁴ The paucity of published, validated, patient-related outcome data on which to gauge the value of surgery and the lack of a standard definition of “benefit” further confuse the objective determination of whether these patients benefit from surgery.

In a cohort with advanced ovarian cancer and bowel obstruction, surgery was detrimental to survival and quality of life for all subgroups, and most patients died in the hospital.⁶

The risk of surgery for malignant bowel obstruction is presumably higher than for abdominal surgery for other indications, since many of the patients are debilitated from their cancer and chemotherapy, and many are malnourished.²³ Even when taking into account a potential selection bias in favor of surgery, several studies have reported no significant difference in 30-day mortality rates or median survival between operative and nonoperative groups.^2,12 Neither the type of obstruction nor the extent of the surgery influenced outcomes. Surgical outcomes are best in patients with a benign cause of obstruction; little benefit is seen in operating on those with abdominal carcinomatosis.¹²

Nevertheless, surgery is beneficial in a select few. For patients with a good performance status, slowly progressive cancer, and an expected survival of more than 6 months, surgical bypass or resection is preferred.^7,12,25 The challenge is to identify these surgical candidates, taking into account prognostic factors such as nutritional status, tumor burden, performance status, presence of ascites, advanced age, extensive prior chemotherapy or radiotherapy, and diffuse carcinomatosis.^{3,10,12,20,23}

Is surgery consistent with the goals of care?

Crucial to decision-making are the goals of care. Since palliative surgery carries a low level of evidence for benefit in terms of quality of life and survival, time should be set aside to thoroughly review the patient’s medical condition, to explore options, and to clarify expectations and goals of care.^3,10 Family members should be invited to be present during these discussions and to be involved in the decision-making process.

WHAT IS THE BENEFIT OF GASTRIC OR COLONIC STENTING?

Endoscopic procedures are alternatives to surgery and offer a palliative option in malignant bowel obstruction. Endoscopic procedures are associated with a shorter hospital stay and quicker recovery than after laparotomy.^9,26–30 In certain situations, stenting serves as a bridge to surgery, allowing time to mitigate comorbid conditions, to enhance nutrition, and to complete staging, while relieving symptoms.^{27–29,31,32} Definitive surgery can be done as a single-stage procedure without a diverting enterostomy.

Self-expanding metal stents for gastric outlet, small-bowel, and colonic obstructions are an option in patients who have incurable metastatic disease who are unfit for surgery, in patients with a single point of obstruction or locally extensive disease, or in patients who do not want to undergo laparotomy.^28–30

Technical and clinical success rates for colorectal stenting are high (88% to 93%).^26,27 Stenting is more successful for left-sided colonic obstructions than for proximal colonic obstructions. Even for patients with extracolonic malignancies such as ovarian cancer, the technical success rate of colorectal stenting is 87%.²⁶ However, patients with unrecognized peritoneal carcinomatosis or multifocal bowel obstruction are less likely to have symptomatic relief even after successful stenting.^6,9

Absolute contraindications to stenting are colonic or tumor perforation with peritonitis. A relative contraindication is a rectal tumor within 2 cm of the anal margin. Stenting in this circumstance leads to tenesmus and incontinence.³³

Complications of stenting

Death rates during colorectal stent insertion are less than 1%. The hospital stay and incidence of complications are significantly less than with surgery.^26,30

Stent migration occurs in 10% of cases and is asymptomatic, but half of patients with this complication require a repeat intervention. The risk of migration is greater if chemotherapy or radiation therapy succeeds in shrinking the tumor.

Bleeding occurs in 5% of cases, usually from the underlying tumor.

Perforation occurs in 4%, but the rate increases to 10% with the use of dilatation before stent placement.

The rate of recurrent obstruction from tumor ingrowth, overgrowth, or fecal impaction is 10%.^9,26,29 Recurrent obstruction may be treated with additional stents inserted within the original stent.⁹

GASTRIC OUTLET OBSTRUCTION: SURGERY VS STENTING

Gastrojejunostomy has in the past been the treatment of choice for gastric outlet obstruction. Certainly, patients with slow-growing tumors and an expected survival of greater than 60 days may be considered for this bypass procedure; those with a short tumor length, a single site of obstruction (preferably in the pylorus or proximal duodenum), a good performance status, and a life expectancy greater than 30 days are good candidates.⁷ Nevertheless, for patients with advanced cancer and poor performance status, gastroenterostomy carries a significant risk of morbidity and death.²⁸

Endoscopic stenting of gastric outlet obstruction has a greater success rate, a shorter time to oral intake, a lower morbidity rate, a lower incidence of delayed gastric emptying, and a shorter hospital stay compared with gastroenterostomy.^28,29 Technical success rates of stenting are 90%, and 75% of patients have resolution of nausea and vomiting.⁷ Stenting is generally not possible if the obstruction occurs beyond the ligament of Treitz.

Patients who are expected to survive less than 1 month or who have rapidly progressive disease, overt ascites, carcinomatosis, or multiple sites of obstruction should be managed with percutaneous, endoscopically placed gastrostomy tubes.⁷

Late complications of stenting for gastric outlet obstruction are occlusion with food or ingrowth of tumor through or around the wire mesh.⁷ This may require laser therapy or placement of a second stent, or both.

DRUG THERAPY

Medical therapy can palliate symptoms of malignant bowel obstruction for most patients.³⁴ Recommendations have been published by the Working Group of the European Association for Palliative Care.²⁴ Symptom management is focused on pain, nausea, and vomiting.

Which drugs can I use for abdominal pain?

Patients experience two types of abdominal pain: continuous and colic. Each type of pain requires different treatment approaches and classes of drugs.

Potent opioids such as morphine, hydromorphone (Dilaudid), and fentanyl (Fentora) are used to relieve continuous abdominal pain.⁷ The dose is titrated for adequate relief. Subcutaneous, intravenous, sublingual, and transdermal routes can be used if nausea and vomiting prevent oral administration.

However, opioids can aggravate colic by stimulating circular smooth muscle, leading to segmental contractions. Opioid-sparing adjuvant drugs such as ketorolac (Toradol) may improve colic and continuous pain and prevent a partial obstruction from becoming a complete obstruction by sparing opioid doses.³⁵

Colic may persist or worsen with the use of opioids. Drugs that reduce colic include the scopolamine drugs hyoscine butylbromide and hyoscine hydrobromide, glycopyrrolate (Robinul), and octreotide (Sandostatin).^7,34–37

Which drugs are appropriate for reducing nausea and vomiting?

Phenothiazines reduce nausea and control vomiting. Chlorpromazine (Thorazine), prochlorperazine (Compro, Compazine), and promethazine (Phenergan) have all been reported to treat nausea successfully.^35,37

Haloperidol (Haldol), a butyrophenone selective dopamine D2-receptor antagonist, has negligible anticholinergic activity. At low doses it produces less sedation than phenothiazines and is an ideal agent for patients with nausea and delirium.³⁵ Doses range from 5 to 15 mg/day, given in divided doses or as intermittent or continuous intravenous infusions.

Anticholinergics, with or without somatostatin analogues, reduce gastrointestinal secretions, fluid accumulation, and vomiting. Anticholinergics bind to muscarinic receptors on enteric neurons in the myenteric and the submucosal plexus. Dosages:

• Hyoscine butylbromide 40 to 120 mg/day.
• Hyoscine hydrobromide 0.2 to 0.9 mg/day.^7,34

Glycopyrrolate, a quaternary ammonium anticholinergic, has minimal central nervous system penetration and is less likely to cause delirium or cardiac side effects compared with tertiary amine anticholinergics such as atropine and scopolamine.³⁸ The recommended dose is 0.1 to 0.2 mg subcutaneously or intravenously three to four times daily.

Octreotide, an analogue of somatostatin, blocks the release of vasoactive intestinal polypeptide, which is increased in malignant bowel obstruction.^14,15 It reduces the excretion of water, sodium, and chloride into the bowel lumen and increases the absorption of electrolytes and water. It also inhibits pancreatic enzyme secretion and splanchnic blood flow. The result of all these effects is reduced luminal content, reduced motility, reduced vascular congestion of the bowel wall, and, in certain circumstances, reduced ascites.³⁹

In small randomized trials, octreotide was more successful than anticholinergics at improving nausea, vomiting, and colic in patients requiring a nasogastric tube and in those whose symptoms were refractory to standard medical treatment.^5,34,40–43 A recent case report found octreotide helpful in resolving symptoms of partial bowel obstruction that were unresponsive to standard measures.⁴⁴

Octreotide is well tolerated and reduces the time patients require a nasogastric tube without significantly worsening xerostomia. High cost limits its use in American hospice care due to the Medicare capitated system of reimbursement for drugs and services, and as a result it is a second-tier drug despite evidence of its efficacy.

Octreotide doses are 100 to 200 mg every 8 hours.

Metoclopramide (Reglan), a dopaminergic antagonist, a 5HT4 receptor agonist, and a 5HT3 receptor blocker at doses greater than 120 mg/day, combines the action of a phenothiazine, which blocks D2 receptors in the central chemoreceptor trigger zone, with promotility actions through serotonin receptors (5HT4).^35,37

Metoclopramide should not be used with anticholinergics or in patients with colic or complete obstruction.^35,45 In some centers it is the first-line drug for functional or partial bowel obstruction.⁷ Dosages range from 40 to 240 mg/day.

Olanzapine (Zyprexa), an atypical antipsychotic, blocks multiple neurotransmitter receptors (D2, H1, Ach, 5HT3) responsible for initiating emesis. It is an option in patients whose nausea and vomiting fail to respond to standard antiemetics.⁴⁶ Dosages range from 2.5 to 20 mg/day.

Dissolvable tablets are given sublingually, which makes olanzapine a versatile antiemetic in cases of intractable nausea. Our unpublished experience is that the sublingual route reduces nausea associated with malignant bowel obstruction and obviates the need for subcutaneous injections or intravenous antiemetic infusions.

Corticosteroids. Although how corticosteroids relieve malignant bowel obstruction is unknown, they are presumed to act centrally.^37,45 In addition, they reduce peritumoral edema and luminal salt and water, and they also have antiemetic and analgesic properties.

Evidence from a meta-analysis found that 6 to 16 mg of parenteral dexamethasone per day reduced symptoms and improved bowel function in 60% of patients but did not change the prognosis.¹¹

A trial of 4 or 5 days is adequate to determine response. If there is no response, the corticosteroid should be rapidly tapered. Side effects are minimal when corticosteroids are used short-term.

Combination therapy. Only rarely does a single drug resolve symptoms of malignant bowel obstruction. Antiemetics, analgesics, corticosteroids, antisecretory anticholinergics, and octreotide are often required in combination to achieve acceptable symptom relief.^3,5,7,47

In a small prospective case series, the combination of metoclopramide 60 mg/day, octreotide 0.3 mg/day, and dexamethasone 12 mg/day with a single bolus of amidotrizoic acid (a contrast agent) improved intestinal transit within 1 to 5 days and resolved vomiting within 24 hours.⁴⁵

Compatibility and the route of administration of medications are key considerations when choosing drug combinations.

WHEN TO CONSIDER A VENTING GASTROSTOMY

Patients with a poor performance status, rapidly progressive disease, peritoneal carcinomatosis, a life expectancy of less than 30 days, or multiple levels of obstruction benefit from placement of a percutaneous endoscopic gastrostomy tube (ie, a venting gastrostomy) rather than surgery if symptoms do not respond to drug therapy.^7,48 There is compelling evidence that this procedure relieves nausea and vomiting in 80% to 90% of patients and restores some level of oral intake in many.^5,6,48,49 A venting gastrostomy tube can be placed during surgical exploration, percutaneously with fluoroscopy, or endoscopically.⁹

There are no absolute contraindications to gastrostomy tube placement. It is feasible even in patients with tumors encasing the stomach, diffuse carcinomatosis, and ascites.⁴⁸ However, massive ascites, previous upper abdominal surgery, or a large mass attached to the abdominal wall make tube placement difficult.

Complications are often local. Patients experience transient abdominal wall pain after the procedure. Dislodgement, bleeding, catheter migration, peritonitis, and necrotizing fasciitis are early complications. Others include skin excoriation from leakage of gastric contents, leakage of ascitic fluid from the site, and obstruction or dislodgement of the tube.^48,49

Patients can be discharged from the hospital soon after the tube is placed, usually with fewer medications than for patients who undergo surgery.⁴⁸ This is particularly important for patients with a short expected survival. Some patients at home benefit from hydration (less than 2 L/day) via an existing central venous port or peripherally inserted central catheter, or by hypodermoclysis.

WHEN IS A NASOGASTRIC TUBE APPROPRIATE?

Some patients with malignant bowel obstruction require a nasogastric tube early in their hospital course.¹² Unfortunately, nasogastric tubes, if left in place, cause nose and throat pain, sinusitis, abscess formation, erosion of nasal cartilage, aspiration, esophageal erosion, pharyngitis, and social isolation.^5,6

Nasogastric tubes should be a temporizing measure to vent gastrointestinal secretions, reduce abdominal distension, and improve nausea and vomiting while a decision about surgery is being made.^13,24 If surgery is not feasible, one can avoid the long-term complications and discomfort of a nasogastric tube via medical management and earlier evaluation for venting gastrostomy in those with symptoms that respond poorly to optimal medical management.⁴⁹

WHICH PATIENTS BENEFIT FROM TOTAL PARENTERAL NUTRITION?

The use of total parenteral nutrition in patients with incurable malignancies is controversial. Enteral and parenteral feeding can increase muscle mass and improve functional status and quality of life in a subset of patients who are not suffering from cancer-related cachexia.^2,50,51 However, for those whose weight loss and malnutrition are consequences of tumor-mediated cachexia, as demonstrated by anorexia and an elevated C-reactive protein level, parenteral nutrition is unlikely to improve the outcome.⁵¹ For most terminally ill patients, retrospective studies have failed to show that parenteral nutrition improves overall survival, performance status, or quality of life.^2,48,50–54

Total parenteral nutrition poses risks: it is invasive and requires central venous access, which predisposes to infection; it requires frequent monitoring of hydration and electrolytes; and it predisposes to thrombosis, diarrhea, hyperglycemia, and liver failure.^50–56

Total parenteral nutrition may be justified in patients with minimal tumor burden who are candidates for definitive surgery, or in those with a good performance status early in the disease course who have not had chemotherapy or whose cancer responds to chemotherapy.^2,50–56

The American College of Physicians discourages the routine use of parenteral nutrition in those with advanced cancer who are undergoing palliative chemotherapy, since few patients benefit and many experience side effects.⁵³

Total parenteral nutrition is much like a medical intervention in that it should be offered or continued only if it provides benefit. Conversations at the time that it is begun must include adverse effects that will lead to its discontinuation, and criteria for response. In certain situations, a limited trial of parenteral nutrition may be considered for patients with an uncertain prognosis or for those who have potentially reversible conditions that limit oral intake.⁵¹ In such cases, there should be a clear understanding between patient and physician that parenteral nutrition will be discontinued if it fails to show benefit.⁵³

ADDITIONAL CONCERNS OF PATIENTS AND FAMILIES

‘Will I starve to death?’

Starvation is a fear echoed by patients and families. Ethical discourse on the continuation of nutrition and hydration for the terminally ill has been polarizing.^57–60 Withdrawal of nutrition can be perceived as euthanasia.

Advanced cancer patients in general do not experience hunger, and those who do require only small amounts of food for satiation.⁶¹ In one report, most patients died of their advanced cancer and not from starvation.⁵² Artificial hydration and nutrition will thus not influence survival and can even be a burden without benefit in the imminently dying.⁶⁰ These patients should be encouraged to take food orally for pleasure, as long as it is tolerated, without consideration of end points such as weight gain, body mass index, or albumin levels.

Complaints of thirst and dryness of the mouth are relieved with mouth care, ice chips, lubrication to the lips, and sips of fluid, rather than by parenteral nutrition.⁵⁹ Patients with a terminal illness experience relief from thirst with minimal intake. The symptom of thirst may be relieved without hydration.^34,61 Adequate hydration requires smaller fluid volumes due to decreased body weight, decreased renal clearance of free water, and decreased insensible water losses from reduced physical activity.⁵⁸

‘Can we continue intravenous hydration so he won’t die of thirst?’

Overzealous intravenous hydration may worsen the symptoms of malignant bowel obstruction. Overhydration can increase secretions in the gut lumen and worsen the secretion-distention-contraction cycle, leading to greater abdominal pain and to nausea and vomiting.⁷ There is a greater risk of fluid overload in these patients, since they have edema and excessive interstitial fluid. Most have a low serum albumin level, which results in movement of fluid from intravascular to interstitial spaces due to reduced colloid osmotic pressure. In these instances, overzealous hydration can lead to respiratory insufficiency and worsening edema.

In spite of numerous discussions in the medical literature of the benefits and burdens of continual hydration, there is no consensus or guideline. When a patient has limited oral intake, the decision to hydrate should be individualized, with careful assessment of the risks and benefits and in accordance with the patient’s or family’s wishes.^57,58

Discharging patients with inoperable malignant bowel obstruction requires careful planning. Patients and family members need to be educated on the use of around-the-clock medications and symptom-targeted, as-needed drugs. Days before discharge, questions about diet need to be clarified. Education about total parenteral nutrition and gastrostomy tube care should be completed before discharge from the hospital.

Drug management should be simplified, or compatible medications should be combined into a single infusion. For example, morphine, glycopyrrolate, and haloperidol or metoclopramide are chemically compatible in standard intravenous solutions and can be combined.

Families feel less anxious about the foreseen and the possible unforeseen course of the illness if they can talk with hospice workers early on. This early involvement also facilitates the transition to home hospice care.

SUMMARY OF IMPORTANT POINTS

• Patients with malignant bowel obstruction need a highly individualized approach, tailored to their medical condition, the prognosis, and the goals of care.
• Surgery should not be routinely undertaken; less-invasive approaches such as gastric or colonic stenting should be considered first.
• Combinations of analgesics, antisecretory drugs, and antiemetics can provide acceptable symptom relief in the inoperable patient.
• A venting gastrostomy should be considered if drug therapy fails to reduce nausea and vomiting to an acceptable level.
• A nasogastric tube should be used only as a temporizing measure, until symptoms are controlled medically or a venting gastrostomy is placed.
• Total parenteral nutrition is of benefit only in patients with intermediate life expectancy who may otherwise die of starvation rather than from the cancer itself.

Malignant bowel obstruction occurs in 5% to 51% of women with ovarian cancer and in 10% to 28% of patients with gastrointestinal cancer, predominantly in the advanced stages.¹ Median survival after its onset ranges from 30 to 90 days.^2–5

Its symptoms are challenging to manage, since nausea, vomiting, colic, and abdominal pain, which are common, cause significant physical distress and demoralization. The decision whether to correct it with surgery requires an individualized approach and a clear understanding of the goals of care and expected survival in the individual patient.

This review focuses on the management of inoperable malignant bowel obstruction and includes discussion of hydration, nutrition, and endoscopic palliative options.

WHAT ARE THE DIFFERENT TYPES OF OBSTRUCTION?

Bowel obstruction may be mechanical or functional, partial or complete, and may occur at one or at many sites. Tumors can impair bowel function in several ways^6–8:

• Intraluminal tumors can occlude the lumen or act as a point of intussusception.
• Intramural tumors can extend to the mucosa and obstruct the lumen or impair peristalsis.
• Mesenteric and omental masses or malignant adhesions can kink or angulate the bowel, creating an extramural obstruction.
• Tumors that infiltrate into the mesentery, bowel muscle, or the enteric or celiac plexus can cause dysmotility.

Cholangiocarcinoma, pancreatic carcinoma, and gallbladder carcinoma are the most common tumors causing duodenal obstruction.⁹ Distal obstruction is caused mainly by colon and ovarian cancer.

Obstruction can be due to treatment

In a minority of patients, obstruction is unrelated to the cancer and is instead due to adhesions arising from surgery, radiation therapy (causing enteritis and strictures), desmoplastic reactions to intraperitoneal chemotherapy, torsion, or internal hernias.^10–12

In rare cases, a patient has intestinal pseudo-obstruction from paraneoplastic destruction of enteric neurons, or severe ileus from anticholinergic or sympathomimetic drugs, as seen with acute colonic pseudo-obstruction (Ogilvie syndrome).¹³

Physiologic reactions to obstruction

Malignant bowel obstruction stimulates gastric, biliary, pancreatic, and intestinal secretions, decreases intraluminal sodium and water reabsorption, and increases mucosal sodium and water secretion.^6,14 In response to the obstruction, peristalsis increases, and prostaglandin, vasoactive intestinal peptide, and nociceptive mediators are released. Vasoactive intestinal polypeptide perpetuates a cycle of secretion, distention, and contraction that leads to intestinal hyperemia, bowel edema, and accumulation of fluid in the lumen.^8,10,11,15

Signs and symptoms depend on the site

The site of obstruction determines the signs and symptoms patients experience.^7,14 Obstructions high in the gastrointestinal tract are associated with greater symptoms but fewer signs than colonic obstructions.¹ Patients with proximal small-bowel obstruction have more severe nausea and a greater number of episodes of emesis, but they have relatively normal plain radiographs of the abdomen, which do not have the characteristic air-fluid levels commonly seen with distal small-bowel obstruction.

Most malignant obstructions remain partial, but increasing abdominal distention, worsening nausea, vomiting, abdominal pain, and obstipation over 1 to 2 weeks¹ suggest progression to complete obstruction.

IMAGING TESTS FOR MALIGNANT BOWEL OBSTRUCTION

What is the value of plain radiography?

Despite these limitations, plain radiography is useful in assessing constipation and its severity as a potential cause of symptoms, and thus it remains an important initial imaging study in almost all patients with suspected malignant bowel obstruction.^17,18 It is also used to assess response to treatment.

When do you need contrast radiographs?

Contrast radiography (barium swallow or barium or Gastrograffin enema) is helpful in patients with symptoms of dysmotility from suspected bowel obstruction. It defines the site or sites of obstruction and the extent of the obstruction with a fair degree of accuracy.^7,19 Single-contrast studies, if positive, exclude opioid-induced bowel dysfunction or pseudo-obstruction in 83% of patients, with a sensitivity and specificity of 96% and 98%, respectively.^8,20 Small-bowel follow-through with barium is more appropriate for low-grade obstructions or for symptomatic patients with a normal kidney, ureter, bladder radiograph.¹⁹

However, contrast radiography is limited by the patient’s ability to swallow barium or water-soluble contrast agents, and it can worsen nausea or vomiting.^17,18 Also, barium is not absorbed systemically and may interfere with subsequent radiologic studies. Large volumes of contrast agents increase the risk of aspiration pneumonia in patients with poorly controlled nausea and can lead to severe impaction proximal to the obstructed site.⁸

Enteroclysis, ie, injecting radiographic contrast into the bowel via a nasoduodenal tube, has some advantages over the barium swallow technique for detecting partial small-bowel obstruction, since it bypasses the stomach and allows for therapeutic decompression as well as direct visualization of the area of concern.^17,18 Enteroclysis radiography objectively gauges severity of intestinal obstruction and bowel wall distensibility, which is an advantage over other imaging studies. Its sensitivity is 100% and specificity 88% in experienced hands.¹⁷ Enteroclysis studies also detect nonobstructing intraluminal tumors when computed tomography (CT) is not diagnostic.^17,18,21

The drawbacks to enteroclysis are that it is technically difficult to perform and that few radiologists are trained in it.

When is CT useful?

CT is the primary imaging study for patients with obstructive symptoms and a history of abdominal malignancy or a palpable abdominal mass^17,20,22,23 (Figure 1). It has a specificity of 100% and a sensitivity of 94%. It plays a major role in decision-making regarding surgery, endoscopy, or palliative interventions,^7,19 as it locates the obstruction and differentiates benign from malignant causes with a fair degree of precision.²²

CT findings in malignant bowel obstruction may include:

• A mass at the site of obstruction or within the original surgical field
• Lymphadenopathy
• Abrupt transitions in luminal diameter or irregular thickening of the bowel wall at the site or sites of obstruction.⁷

SURGERY: A DIFFICULT DECISION

Is the patient fit for surgery?

Surgery for malignant bowel obstruction should not be done in patients who have advanced malignancies with bulky intra-abdominal metastases or cancer that has spread outside the abdominal cavity without taking into account treatment options for the cancer, the patient’s nutritional status, and the goals of care.

The role of abdominal surgery (debulking, resection, or bypass) in advanced cancer remains unclear and controversial.²⁴ From 42% to 80% of patients report that symptoms improve after surgery, but recurrent obstruction occurs in 10% to 50%.¹⁰ Even in patients with low tumor bulk and good nutritional status, 30-day mortality rates range from 5% to 40%, and complication rates range from 9% to 90%.^{3,4,6,7,10,14}

Outcomes after surgery depend on patient selection criteria perhaps as much as on the surgeon’s experience and skill. Patients with more advanced cancer who have had multiple surgical procedures and those with cancer that does not respond to chemotherapy and radiation present the greatest challenge to surgeons.²³

What is the benefit of surgery?

Reports of palliative surgery have included information about 60-day survival rates after the operation, but a number of factors may be more meaningful in this context, such as postoperative symptoms, the patient’s overall wellbeing, how the original symptoms respond to the surgery, complications, and length of hospitalization.¹⁴ The paucity of published, validated, patient-related outcome data on which to gauge the value of surgery and the lack of a standard definition of “benefit” further confuse the objective determination of whether these patients benefit from surgery.

In a cohort with advanced ovarian cancer and bowel obstruction, surgery was detrimental to survival and quality of life for all subgroups, and most patients died in the hospital.⁶

The risk of surgery for malignant bowel obstruction is presumably higher than for abdominal surgery for other indications, since many of the patients are debilitated from their cancer and chemotherapy, and many are malnourished.²³ Even when taking into account a potential selection bias in favor of surgery, several studies have reported no significant difference in 30-day mortality rates or median survival between operative and nonoperative groups.^2,12 Neither the type of obstruction nor the extent of the surgery influenced outcomes. Surgical outcomes are best in patients with a benign cause of obstruction; little benefit is seen in operating on those with abdominal carcinomatosis.¹²

Nevertheless, surgery is beneficial in a select few. For patients with a good performance status, slowly progressive cancer, and an expected survival of more than 6 months, surgical bypass or resection is preferred.^7,12,25 The challenge is to identify these surgical candidates, taking into account prognostic factors such as nutritional status, tumor burden, performance status, presence of ascites, advanced age, extensive prior chemotherapy or radiotherapy, and diffuse carcinomatosis.^{3,10,12,20,23}

Is surgery consistent with the goals of care?

Crucial to decision-making are the goals of care. Since palliative surgery carries a low level of evidence for benefit in terms of quality of life and survival, time should be set aside to thoroughly review the patient’s medical condition, to explore options, and to clarify expectations and goals of care.^3,10 Family members should be invited to be present during these discussions and to be involved in the decision-making process.

WHAT IS THE BENEFIT OF GASTRIC OR COLONIC STENTING?

Endoscopic procedures are alternatives to surgery and offer a palliative option in malignant bowel obstruction. Endoscopic procedures are associated with a shorter hospital stay and quicker recovery than after laparotomy.^9,26–30 In certain situations, stenting serves as a bridge to surgery, allowing time to mitigate comorbid conditions, to enhance nutrition, and to complete staging, while relieving symptoms.^{27–29,31,32} Definitive surgery can be done as a single-stage procedure without a diverting enterostomy.

Self-expanding metal stents for gastric outlet, small-bowel, and colonic obstructions are an option in patients who have incurable metastatic disease who are unfit for surgery, in patients with a single point of obstruction or locally extensive disease, or in patients who do not want to undergo laparotomy.^28–30

Technical and clinical success rates for colorectal stenting are high (88% to 93%).^26,27 Stenting is more successful for left-sided colonic obstructions than for proximal colonic obstructions. Even for patients with extracolonic malignancies such as ovarian cancer, the technical success rate of colorectal stenting is 87%.²⁶ However, patients with unrecognized peritoneal carcinomatosis or multifocal bowel obstruction are less likely to have symptomatic relief even after successful stenting.^6,9

Absolute contraindications to stenting are colonic or tumor perforation with peritonitis. A relative contraindication is a rectal tumor within 2 cm of the anal margin. Stenting in this circumstance leads to tenesmus and incontinence.³³

Complications of stenting

Death rates during colorectal stent insertion are less than 1%. The hospital stay and incidence of complications are significantly less than with surgery.^26,30

Stent migration occurs in 10% of cases and is asymptomatic, but half of patients with this complication require a repeat intervention. The risk of migration is greater if chemotherapy or radiation therapy succeeds in shrinking the tumor.

Bleeding occurs in 5% of cases, usually from the underlying tumor.

Perforation occurs in 4%, but the rate increases to 10% with the use of dilatation before stent placement.

The rate of recurrent obstruction from tumor ingrowth, overgrowth, or fecal impaction is 10%.^9,26,29 Recurrent obstruction may be treated with additional stents inserted within the original stent.⁹

GASTRIC OUTLET OBSTRUCTION: SURGERY VS STENTING

Gastrojejunostomy has in the past been the treatment of choice for gastric outlet obstruction. Certainly, patients with slow-growing tumors and an expected survival of greater than 60 days may be considered for this bypass procedure; those with a short tumor length, a single site of obstruction (preferably in the pylorus or proximal duodenum), a good performance status, and a life expectancy greater than 30 days are good candidates.⁷ Nevertheless, for patients with advanced cancer and poor performance status, gastroenterostomy carries a significant risk of morbidity and death.²⁸

Endoscopic stenting of gastric outlet obstruction has a greater success rate, a shorter time to oral intake, a lower morbidity rate, a lower incidence of delayed gastric emptying, and a shorter hospital stay compared with gastroenterostomy.^28,29 Technical success rates of stenting are 90%, and 75% of patients have resolution of nausea and vomiting.⁷ Stenting is generally not possible if the obstruction occurs beyond the ligament of Treitz.

Patients who are expected to survive less than 1 month or who have rapidly progressive disease, overt ascites, carcinomatosis, or multiple sites of obstruction should be managed with percutaneous, endoscopically placed gastrostomy tubes.⁷

Late complications of stenting for gastric outlet obstruction are occlusion with food or ingrowth of tumor through or around the wire mesh.⁷ This may require laser therapy or placement of a second stent, or both.

DRUG THERAPY

Medical therapy can palliate symptoms of malignant bowel obstruction for most patients.³⁴ Recommendations have been published by the Working Group of the European Association for Palliative Care.²⁴ Symptom management is focused on pain, nausea, and vomiting.

Which drugs can I use for abdominal pain?

Patients experience two types of abdominal pain: continuous and colic. Each type of pain requires different treatment approaches and classes of drugs.

Potent opioids such as morphine, hydromorphone (Dilaudid), and fentanyl (Fentora) are used to relieve continuous abdominal pain.⁷ The dose is titrated for adequate relief. Subcutaneous, intravenous, sublingual, and transdermal routes can be used if nausea and vomiting prevent oral administration.

However, opioids can aggravate colic by stimulating circular smooth muscle, leading to segmental contractions. Opioid-sparing adjuvant drugs such as ketorolac (Toradol) may improve colic and continuous pain and prevent a partial obstruction from becoming a complete obstruction by sparing opioid doses.³⁵

Colic may persist or worsen with the use of opioids. Drugs that reduce colic include the scopolamine drugs hyoscine butylbromide and hyoscine hydrobromide, glycopyrrolate (Robinul), and octreotide (Sandostatin).^7,34–37

Which drugs are appropriate for reducing nausea and vomiting?

Phenothiazines reduce nausea and control vomiting. Chlorpromazine (Thorazine), prochlorperazine (Compro, Compazine), and promethazine (Phenergan) have all been reported to treat nausea successfully.^35,37

Haloperidol (Haldol), a butyrophenone selective dopamine D2-receptor antagonist, has negligible anticholinergic activity. At low doses it produces less sedation than phenothiazines and is an ideal agent for patients with nausea and delirium.³⁵ Doses range from 5 to 15 mg/day, given in divided doses or as intermittent or continuous intravenous infusions.

Anticholinergics, with or without somatostatin analogues, reduce gastrointestinal secretions, fluid accumulation, and vomiting. Anticholinergics bind to muscarinic receptors on enteric neurons in the myenteric and the submucosal plexus. Dosages:

• Hyoscine butylbromide 40 to 120 mg/day.
• Hyoscine hydrobromide 0.2 to 0.9 mg/day.^7,34

Glycopyrrolate, a quaternary ammonium anticholinergic, has minimal central nervous system penetration and is less likely to cause delirium or cardiac side effects compared with tertiary amine anticholinergics such as atropine and scopolamine.³⁸ The recommended dose is 0.1 to 0.2 mg subcutaneously or intravenously three to four times daily.

Octreotide, an analogue of somatostatin, blocks the release of vasoactive intestinal polypeptide, which is increased in malignant bowel obstruction.^14,15 It reduces the excretion of water, sodium, and chloride into the bowel lumen and increases the absorption of electrolytes and water. It also inhibits pancreatic enzyme secretion and splanchnic blood flow. The result of all these effects is reduced luminal content, reduced motility, reduced vascular congestion of the bowel wall, and, in certain circumstances, reduced ascites.³⁹

In small randomized trials, octreotide was more successful than anticholinergics at improving nausea, vomiting, and colic in patients requiring a nasogastric tube and in those whose symptoms were refractory to standard medical treatment.^5,34,40–43 A recent case report found octreotide helpful in resolving symptoms of partial bowel obstruction that were unresponsive to standard measures.⁴⁴

Octreotide is well tolerated and reduces the time patients require a nasogastric tube without significantly worsening xerostomia. High cost limits its use in American hospice care due to the Medicare capitated system of reimbursement for drugs and services, and as a result it is a second-tier drug despite evidence of its efficacy.

Octreotide doses are 100 to 200 mg every 8 hours.

Metoclopramide (Reglan), a dopaminergic antagonist, a 5HT4 receptor agonist, and a 5HT3 receptor blocker at doses greater than 120 mg/day, combines the action of a phenothiazine, which blocks D2 receptors in the central chemoreceptor trigger zone, with promotility actions through serotonin receptors (5HT4).^35,37

Metoclopramide should not be used with anticholinergics or in patients with colic or complete obstruction.^35,45 In some centers it is the first-line drug for functional or partial bowel obstruction.⁷ Dosages range from 40 to 240 mg/day.

Olanzapine (Zyprexa), an atypical antipsychotic, blocks multiple neurotransmitter receptors (D2, H1, Ach, 5HT3) responsible for initiating emesis. It is an option in patients whose nausea and vomiting fail to respond to standard antiemetics.⁴⁶ Dosages range from 2.5 to 20 mg/day.

Dissolvable tablets are given sublingually, which makes olanzapine a versatile antiemetic in cases of intractable nausea. Our unpublished experience is that the sublingual route reduces nausea associated with malignant bowel obstruction and obviates the need for subcutaneous injections or intravenous antiemetic infusions.

Corticosteroids. Although how corticosteroids relieve malignant bowel obstruction is unknown, they are presumed to act centrally.^37,45 In addition, they reduce peritumoral edema and luminal salt and water, and they also have antiemetic and analgesic properties.

Evidence from a meta-analysis found that 6 to 16 mg of parenteral dexamethasone per day reduced symptoms and improved bowel function in 60% of patients but did not change the prognosis.¹¹

A trial of 4 or 5 days is adequate to determine response. If there is no response, the corticosteroid should be rapidly tapered. Side effects are minimal when corticosteroids are used short-term.

Combination therapy. Only rarely does a single drug resolve symptoms of malignant bowel obstruction. Antiemetics, analgesics, corticosteroids, antisecretory anticholinergics, and octreotide are often required in combination to achieve acceptable symptom relief.^3,5,7,47

In a small prospective case series, the combination of metoclopramide 60 mg/day, octreotide 0.3 mg/day, and dexamethasone 12 mg/day with a single bolus of amidotrizoic acid (a contrast agent) improved intestinal transit within 1 to 5 days and resolved vomiting within 24 hours.⁴⁵

Compatibility and the route of administration of medications are key considerations when choosing drug combinations.

WHEN TO CONSIDER A VENTING GASTROSTOMY

Patients with a poor performance status, rapidly progressive disease, peritoneal carcinomatosis, a life expectancy of less than 30 days, or multiple levels of obstruction benefit from placement of a percutaneous endoscopic gastrostomy tube (ie, a venting gastrostomy) rather than surgery if symptoms do not respond to drug therapy.^7,48 There is compelling evidence that this procedure relieves nausea and vomiting in 80% to 90% of patients and restores some level of oral intake in many.^5,6,48,49 A venting gastrostomy tube can be placed during surgical exploration, percutaneously with fluoroscopy, or endoscopically.⁹

There are no absolute contraindications to gastrostomy tube placement. It is feasible even in patients with tumors encasing the stomach, diffuse carcinomatosis, and ascites.⁴⁸ However, massive ascites, previous upper abdominal surgery, or a large mass attached to the abdominal wall make tube placement difficult.

Complications are often local. Patients experience transient abdominal wall pain after the procedure. Dislodgement, bleeding, catheter migration, peritonitis, and necrotizing fasciitis are early complications. Others include skin excoriation from leakage of gastric contents, leakage of ascitic fluid from the site, and obstruction or dislodgement of the tube.^48,49

Patients can be discharged from the hospital soon after the tube is placed, usually with fewer medications than for patients who undergo surgery.⁴⁸ This is particularly important for patients with a short expected survival. Some patients at home benefit from hydration (less than 2 L/day) via an existing central venous port or peripherally inserted central catheter, or by hypodermoclysis.

WHEN IS A NASOGASTRIC TUBE APPROPRIATE?

Some patients with malignant bowel obstruction require a nasogastric tube early in their hospital course.¹² Unfortunately, nasogastric tubes, if left in place, cause nose and throat pain, sinusitis, abscess formation, erosion of nasal cartilage, aspiration, esophageal erosion, pharyngitis, and social isolation.^5,6

Nasogastric tubes should be a temporizing measure to vent gastrointestinal secretions, reduce abdominal distension, and improve nausea and vomiting while a decision about surgery is being made.^13,24 If surgery is not feasible, one can avoid the long-term complications and discomfort of a nasogastric tube via medical management and earlier evaluation for venting gastrostomy in those with symptoms that respond poorly to optimal medical management.⁴⁹

WHICH PATIENTS BENEFIT FROM TOTAL PARENTERAL NUTRITION?

The use of total parenteral nutrition in patients with incurable malignancies is controversial. Enteral and parenteral feeding can increase muscle mass and improve functional status and quality of life in a subset of patients who are not suffering from cancer-related cachexia.^2,50,51 However, for those whose weight loss and malnutrition are consequences of tumor-mediated cachexia, as demonstrated by anorexia and an elevated C-reactive protein level, parenteral nutrition is unlikely to improve the outcome.⁵¹ For most terminally ill patients, retrospective studies have failed to show that parenteral nutrition improves overall survival, performance status, or quality of life.^2,48,50–54

Total parenteral nutrition poses risks: it is invasive and requires central venous access, which predisposes to infection; it requires frequent monitoring of hydration and electrolytes; and it predisposes to thrombosis, diarrhea, hyperglycemia, and liver failure.^50–56

Total parenteral nutrition may be justified in patients with minimal tumor burden who are candidates for definitive surgery, or in those with a good performance status early in the disease course who have not had chemotherapy or whose cancer responds to chemotherapy.^2,50–56

The American College of Physicians discourages the routine use of parenteral nutrition in those with advanced cancer who are undergoing palliative chemotherapy, since few patients benefit and many experience side effects.⁵³

Total parenteral nutrition is much like a medical intervention in that it should be offered or continued only if it provides benefit. Conversations at the time that it is begun must include adverse effects that will lead to its discontinuation, and criteria for response. In certain situations, a limited trial of parenteral nutrition may be considered for patients with an uncertain prognosis or for those who have potentially reversible conditions that limit oral intake.⁵¹ In such cases, there should be a clear understanding between patient and physician that parenteral nutrition will be discontinued if it fails to show benefit.⁵³

ADDITIONAL CONCERNS OF PATIENTS AND FAMILIES

‘Will I starve to death?’

Starvation is a fear echoed by patients and families. Ethical discourse on the continuation of nutrition and hydration for the terminally ill has been polarizing.^57–60 Withdrawal of nutrition can be perceived as euthanasia.

Advanced cancer patients in general do not experience hunger, and those who do require only small amounts of food for satiation.⁶¹ In one report, most patients died of their advanced cancer and not from starvation.⁵² Artificial hydration and nutrition will thus not influence survival and can even be a burden without benefit in the imminently dying.⁶⁰ These patients should be encouraged to take food orally for pleasure, as long as it is tolerated, without consideration of end points such as weight gain, body mass index, or albumin levels.

Complaints of thirst and dryness of the mouth are relieved with mouth care, ice chips, lubrication to the lips, and sips of fluid, rather than by parenteral nutrition.⁵⁹ Patients with a terminal illness experience relief from thirst with minimal intake. The symptom of thirst may be relieved without hydration.^34,61 Adequate hydration requires smaller fluid volumes due to decreased body weight, decreased renal clearance of free water, and decreased insensible water losses from reduced physical activity.⁵⁸

‘Can we continue intravenous hydration so he won’t die of thirst?’

Overzealous intravenous hydration may worsen the symptoms of malignant bowel obstruction. Overhydration can increase secretions in the gut lumen and worsen the secretion-distention-contraction cycle, leading to greater abdominal pain and to nausea and vomiting.⁷ There is a greater risk of fluid overload in these patients, since they have edema and excessive interstitial fluid. Most have a low serum albumin level, which results in movement of fluid from intravascular to interstitial spaces due to reduced colloid osmotic pressure. In these instances, overzealous hydration can lead to respiratory insufficiency and worsening edema.

In spite of numerous discussions in the medical literature of the benefits and burdens of continual hydration, there is no consensus or guideline. When a patient has limited oral intake, the decision to hydrate should be individualized, with careful assessment of the risks and benefits and in accordance with the patient’s or family’s wishes.^57,58

Discharging patients with inoperable malignant bowel obstruction requires careful planning. Patients and family members need to be educated on the use of around-the-clock medications and symptom-targeted, as-needed drugs. Days before discharge, questions about diet need to be clarified. Education about total parenteral nutrition and gastrostomy tube care should be completed before discharge from the hospital.

Drug management should be simplified, or compatible medications should be combined into a single infusion. For example, morphine, glycopyrrolate, and haloperidol or metoclopramide are chemically compatible in standard intravenous solutions and can be combined.

Families feel less anxious about the foreseen and the possible unforeseen course of the illness if they can talk with hospice workers early on. This early involvement also facilitates the transition to home hospice care.

SUMMARY OF IMPORTANT POINTS

• Patients with malignant bowel obstruction need a highly individualized approach, tailored to their medical condition, the prognosis, and the goals of care.
• Surgery should not be routinely undertaken; less-invasive approaches such as gastric or colonic stenting should be considered first.
• Combinations of analgesics, antisecretory drugs, and antiemetics can provide acceptable symptom relief in the inoperable patient.
• A venting gastrostomy should be considered if drug therapy fails to reduce nausea and vomiting to an acceptable level.
• A nasogastric tube should be used only as a temporizing measure, until symptoms are controlled medically or a venting gastrostomy is placed.
• Total parenteral nutrition is of benefit only in patients with intermediate life expectancy who may otherwise die of starvation rather than from the cancer itself.

Dronedarone (Multaq), approved by the US Food and Drug Administration in July 2009, is a congener of the antiarrhythmic drug amiodarone (Cordarone). Designed in the hope that it would be safer than amiodarone, its official indication is to lower the risk of hospitalization in patients with paroxysmal or persistent atrial fibrillation or atrial flutter. However, its precise role in the management of atrial fibrillation is yet to be defined. If dronedarone remains well tolerated, it may permit clinicians to pursue a rhythm control strategy more often. In this article, we present a progress report on this new agent.

BETTER ANTIARRHYTHMIC DRUGS ARE NEEDED

Atrial fibrillation increases the risk of stroke fivefold and accounts for 15% to 20% of all strokes.¹ It also increases the risk of heart failure. Drugs are the mainstay of therapy, but many antiarrhythmic drugs are not very effective and cause cardiac and extracardiac toxicity. Thus, the need for safe and effective new drugs.²

Much effort is going into the development of drugs that target specific ion channels or proteins expressed predominantly in atrial myocardium. The rationale is to avoid the unwanted effects of ionic currents on the ventricle and thus avoid ventricular proarrhythmic effects. At the same time, alternatives to the multiple channel blocker amiodarone, the mainstay of heart rhythm control therapy in atrial fibrillation, are being developed to retain the electrophysiologic efficacy of the mother compound but avoid its extracardiac toxicity.

RATE CONTROL VS RHYTHM CONTROL

In the acute care setting, heart rate control with atrioventricular nodal agents (beta-blockers, calcium channel blockers, and digitalis) is the preferred initial strategy in most hemodynamically stable patients presenting with new-onset atrial fibrillation.³

Since we lack an effective method for maintaining sinus rhythm without incurring significant adverse effects, rate control is also often chosen for chronic management of atrial fibrillation. This is particularly true for patients who have no symptoms or only minimal symptoms and in whom adequate rate control is easily attained. Indeed, results of large clinical trials suggest that rate control is satisfactory for many patients.

The main purpose of rate control is to control symptoms as opposed to merely lowering the ventricular rate. Effective rate control often prevents hemodynamic instability in patients with underlying heart disease who present acutely with atrial fibrillation. In patients with permanent atrial fibrillation, the RACE II study⁴ (Rate Control Efficacy in Permanent Atrial Fibrillation: a Comparison between Lenient Versus Strict Rate Control II), during a 3-year follow-up, showed that lenient rate control (resting heart rate < 110 beats per minute) is not inferior to strict rate control (resting heart rate < 80 beats per minute) in preventing major cardiovascular events (heart failure, stroke) or arrhythmic events such as syncope and sustained ventricular tachycardia.⁴

As a long-term strategy, rate control also prevents tachycardia-induced cardiomyopathy, reduces the risk of worsening of underlying heart failure, and can improve symptoms and quality of life.

Although maintenance of sinus rhythm is most likely associated with a survival benefit, heart rhythm control with antiarrhythmic drugs has not shown an advantage over rate control in overall or cardiovascular death rates, thromboembolic complications, or impact on heart failure. Indeed, a rhythm control strategy has been associated only with better exercise tolerance and, although less clear, with better quality of life.⁵

One possible explanation as to why a rhythm control strategy has not been shown to be superior to a rate control strategy is the side effects of the presently available drugs for rhythm control.

In a subgroup analysis of the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial,⁶ antiarrhythmic therapy was associated with a 49% increase in the mortality rate that offset the benefits of conversion and maintenance of sinus rhythm, which was associated with a 53% reduction in mortality rates.

The hope is that newer drugs with less toxicity may produce better outcomes for patients treated with rhythm control.

AN ANALOGUE OF AMIODARONE, WITHOUT THE IODINE

Dronedarone is a structurally modified version of amiodarone, the antiarrhythmic drug that has shown the greatest efficacy at maintaining sinus rhythm in patients with paroxysmal atrial fibrillation. Although historically amiodarone has been effective in maintaining sinus rhythm and has been used safely in patients with advanced heart failure, its use has been limited by cumulative and often irreversible extracardiac organ toxicity.

Dronedarone was designed to match amiodarone’s efficacy but with a better safety profile. An iodine radical makes up more than one-third of amiodarone’s molecular weight. The omission of iodine in dronedarone was intended to reduce the likelihood of toxic side effects.

Dronedarone is a benzofuran derivative pharmacologically related to amiodarone, with the addition of a methylsulfonamide group. This reduces lipophilicity and the propensity to cross the blood-brain barrier; over a 2-year period this drug has not been shown to have neurotoxic effects.⁷

Dronedarone has proved efficacious without toxic or proarrhythmic effects and has minimal side effects, but concerns remain regarding its use in advanced heart failure. To date, its adverse-event profile appears comparable to that of placebo. However, whether its efficacy and incidence of adverse effects are comparable to what has been reported in the literature may take time to assess.

DRONEDARONE’S PHARMACOLOGY

Dronedarone, like amiodarone, blocks multiple sodium and potassium ion channels. It also exerts an antiadrenergic effect by noncompetitive binding to beta-adrenergic receptors as well as by inhibiting an agonist-induced increase in adenylate cyclase activity.⁸ Compared with amiodarone, dronedarone is a more potent blocker of peak sodium current.

Dronedarone is largely metabolized by the hepatic enzyme cytochrome P450 3A4 isoform (CYP3A4). Only 6% of dronedarone is excreted renally; however, no trial has yet assessed dronedarone’s safety in patients with marked kidney dysfunction.⁸⁹

Dronedarone’s steady-state terminal elimination half-life is approximately 30 hours. When taken twice a day, it achieves steady-state concentrations in 5 to 7 days.

Dronedarone is available only for oral administration at 400 mg twice daily. Dose adjustment or titration is not recommended.

CLINICAL TRIALS OF DRONEDARONE

Dronedarone vs placebo

ATHENA (A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg bid for the Prevention of Cardiovascular Hospitalization or Death From any Cause in Patients With Atrial Fibrillation/Atrial Flutter)¹⁰ was a prospective, double-blind study to assess morbidity and death rates in 4,628 patients with atrial fibrillation or atrial flutter and at least one other cardiovascular risk factor.

EURIDIS and ADONIS. Two trials,¹¹ EURIDIS (European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm) and ADONIS (American-Australian Trial With Dronedarone in Atrial Fibrillation or Flutter Patients for the Maintenance of Sinus Rhythm), enrolled a total of more than 1,200 patients and showed that dronedarone 400 mg twice a day produced a significantly lower rate of recurrence of atrial fibrillation after electrical cardioversion compared with placebo.

Overall, treatment with dronedarone significantly reduced the risk of a first recurrence of atrial fibrillation by 22% (ADONIS) and 27.5% (EURIDIS) (Table 1).

ERATO (Efficacy and Safety of Dronedarone for the Control of Ventricular Rate During Atrial Fibrillation),¹² an additional phase III study, showed that dronedarone controlled the heart rate in patients with persistently accelerated ventricular rates despite concomitant standard therapy with a beta-blocker, digitalis, or a calcium-channel blocker. Dronedarone reduced the mean 24-hour heart rate by 11.7 beats per minute and the maximal exercise ventricular rate by 24.5 beats per minute at the 14th day.

ANDROMEDA (Anti-arrhythmic Trial With Dronedarone in Moderate to Severe CHF Evaluating Morbidity Decrease)¹³ was a study not of patients with atrial fibrillation but rather of patients with symptomatic congestive heart failure, a left ventricular ejection fraction of 35% or less, and recent hospitalization with new or worsening heart failure. The study was terminated early because of a higher rate of death with dronedarone¹³ (Table 1).

Dronedarone vs amiodarone

DIONYSOS (Efficacy and Safety of Dronedarone Versus Amiodarone for the Maintenance of Sinus Rhythm in Patients With Atrial Fibrillation)¹⁴ was a randomized double-blind trial. It evaluated the efficacy and safety of dronedarone (400 mg twice daily) or amiodarone (600 mg daily for 28 days, then 200 mg daily thereafter) for at least 6 months for the maintenance of sinus rhythm in patients with atrial fibrillation. It enrolled 504 patients with persistent atrial fibrillation; patients had not previously taken amiodarone. Dronedarone was less effective than amiodarone in maintaining sinus rhythm: the rate of recurrent atrial fibrillation was 63% with dronedarone and 42% with amiodarone. But dronedarone was associated with fewer adverse effects and less need for premature discontinuation of drug treatment at a mean follow-up of 7 months (Table 1).

WHERE DOES DRONEDARONE FIT IN ATRIAL FIBRILLATION MANAGEMENT?

Dronedarone is indicated in persistent or paroxysmal atrial fibrillation, based on the observed reduction of the rate of hospitalization. It is indicated for the maintenance of sinus rhythm and may be used in patients with persistent or paroxysmal atrial fibrillation and flutter who are in sinus rhythm or will be undergoing cardioversion soon after starting the drug. Dronedarone has no role in the acute management of atrial fibrillation, such as in cardioversion to sinus rhythm in the emergency department.

We do not have substantial evidence of the efficacy of dronedarone in patients with resistant atrial fibrillation, in whom multiple antiarrhythmics have failed to maintain sinus rhythm, and no published trial has used the inclusion criterion of treatment failure with other antiarrhythmic drugs.

The role of dronedarone in heart failure with preserved systolic function is unclear. Patients taking dronedarone are twice as likely as those taking amiodarone to have a recurrence of atrial fibrillation.

The main advantage of dronedarone is its lower adverse effect profile. However, this statement is based on only a few years of observation. If the patient has developed adverse effects with amiodarone, or if the clinician is concerned about the risk of serious adverse effects, dronedarone presents an alternative for those patients without heart failure or significant left ventricular dysfunction. One such group may be younger patients, because of concerns about the cumulative effects of amiodarone taken over a lifetime.

Dronedarone may represent an acceptable alternative to many of the current antiarrhythmic drugs. Based on the results of the Cardiac Arrhythmia Suppression Trial (CAST),¹⁵ class IC antiarrhythmics such as flecainide (Tambocor) are generally avoided in patients with prior myocardial infarction or with known or even suspected coronary artery disease. Similarly, sotalol (Betapace) is generally avoided in patients with marked left ventricular hypertrophy because of adverse effects.¹⁶ Dofetilide (Tikosyn) and often sotalol require hospitalization with telemetric monitoring for QTc prolongation and the risk of proarrhythmia with torsades de pointes. Dronedarone, however, generally can be safely started in the outpatient setting.

As when considering prescribing any antiarrhythmic, the clinician must assess the patient’s thromboembolic risk, since this risk persists with a rhythm control strategy.

There is substantial evidence from the ATHENA trial,¹⁰ in which 30% of the patients had coronary artery disease, that dronedarone is safe and effective in patients with coronary artery disease. Its use in patients who have undergone coronary artery bypass surgery remains to be defined.

WHEN SHOULD WE SWITCH PATIENTS TO DRONEDARONE?

Preliminary experience suggests that dronedarone, unlike most antiarrhythmic drugs, can be safely started about 48 hours after amiodarone is discontinued. Cumulative toxicity has not been noted with dronedarone. Caution should be exercised when switching if the patient has baseline bradycardia or QT interval prolongation. No algorithm has been developed for switching from other antiarrhythmic drugs to dronedarone.

CONTRAINDICATIONS TO DRONEDARONE

Dronedarone is contraindicated in:

• Patients with New York Heart Association (NYHA) class IV heart failure or NYHA class II or III heart failure with recent decompensation requiring hospitalization or referral to a specialized heart failure clinic
• Patients with second- or third-degree atrioventricular block or sick sinus syndrome (except when used in conjunction with a functioning pacemaker) or bradycardia (a heart rate < 50 beats per minute)
• Patients with a QTc interval of 500 ms or longer
• Patients with severe hepatic impairment
• Women who are pregnant, are attempting to become pregnant, or are breast-feeding
• Patients taking potent CYP3A inhibitors—antifungals like ketoconazole (Nizoral), itraconazole (Sporanox), or voriconazole (VFEND); macrolide antibiotics like telithromycin (Ketek) or clarithromycin (Biaxin); protease inhibitors; or other drugs that prolong the QT interval.

In patients with new or worsening heart failure, one should consider suspending or stopping dronedarone therapy.

DRONEDARONE’S ADVERSE EFFECTS

In trials to date, dronedarone has not shown evidence of proarrhythmia (tachyarrhythmia or bradyarrythmia), torsades de pointes, or amiodarone-like organ toxicity affecting the thyroid or the lungs. Recently, rare cases of severe hepatic injury were associated with dronedarone; therefore, periodic liver function testing is advised for patients taking dronedarone, especially during the first 6 months of therapy.

Dronedarone has been associated with higher rates of diarrhea, nausea, bradycardia, QT interval prolongation, and cutaneous rash compared with placebo. In DAFNE (Dronedarone Atrial Fibrillation Study After Electrical Cardioversion),¹⁷ 10.8% of patients taking dronedarone had to stop taking it because of adverse events. With 800 mg daily, the discontinuation rate was only 3.9%. The most common cause of drug discontinuation was gastrointestinal effects. Anecdotal reports suggest that the gastrointestinal side effects may be self-limited and may not always require discontinuation of the drug.

Serum creatinine levels increase by about 0.1 mg/dL after the start of treatment. This elevation occurs after 1 to 2 days, reaches a plateau after 7 days, and is reversible. The mechanism is thought to be that dronedarone partially inhibits tubular organic cation transporters, which in turn reduces renal creatinine clearance by about 18%, but with no evidence of an effect on glomerular filtration, renal plasma flow, or electrolyte exchanges.¹⁸ A limited increase in serum creatinine is, therefore, expected with dronedarone treatment, but this does not mean there is a decline in renal function.

DRONEDARONE AND POTENTIAL DRUG INTERACTIONS

Warfarin. Dronedarone does not increase the international normalized ratio when used with warfarin (Coumadin).

Verapamil, diltiazem. Dose reduction is required to avoid bradyarrhythmias with co-administration of moderate CYP3A4 inhibitors such as verapamil (Calan, Verelan) and diltiazem (Cardizem).

Simvastatin. Dronedarone increases levels of simvastatin (Zocor), a CYP3A4 substrate, two to four times, thus increasing the risk of statin-induced myopathy.

Digoxin. Dronedarone increases the serum digoxin concentration about 2.5 times, and this necessitates monitoring the digoxin level and possibly reducing the digoxin dose.¹³

Diuretics. Hypokalemia and hypomagnesemia may occur with concomitant administration of potassium-depleting diuretics. Potassium levels should be maintained in the normal range before and during administration of dronedarone.

Tacrolimus, sirolimus. Dronedarone may increase levels of tacrolimus (Prograf) or sirolimus (Rapamune) in posttransplantation patients. This requires dose monitoring and adjustment in concomitant therapy with these agents.

COST VARIES

The cost of dronedarone varies based on factors that include location. Dronedarone’s retail cost ranges from $3.20 to $4.00 per pill (approximately $7.20 per day). It is not available in generic form. It is presently covered by many health plans as a tier 2 drug, representing a $15 to $40 monthly copay.

MORE DATA NEEDED

Dronedarone represents the first in what may well be a number of new antiarrhythmic drugs for the treatment of patients with paroxysmal atrial fibrillation. Although less efficacious then amiodarone, dronedarone appears to be better tolerated and have less serious side effects. It is contraindicated in patients with severe systolic dysfunction and in those with recent heart failure decompensation. It appears safe in coronary artery disease and marked left ventricular hypertrophy, unlike flecainide, propafenone (Rythmol), and sotalol.

To further understand how dronedarone will fare against other antiarrhythmic drugs, more studies with longer follow-up are needed. These studies need to demonstrate superior tolerability of dronedarone, acceptable quality of life without unacceptable loss of efficacy, or a decrease in morbidity or mortality rates compared with amiodarone.

Dronedarone can be safely started in most patients on an outpatient basis. The risk of proarrhythmia with dronedarone appears to be very low.

Dronedarone (Multaq), approved by the US Food and Drug Administration in July 2009, is a congener of the antiarrhythmic drug amiodarone (Cordarone). Designed in the hope that it would be safer than amiodarone, its official indication is to lower the risk of hospitalization in patients with paroxysmal or persistent atrial fibrillation or atrial flutter. However, its precise role in the management of atrial fibrillation is yet to be defined. If dronedarone remains well tolerated, it may permit clinicians to pursue a rhythm control strategy more often. In this article, we present a progress report on this new agent.

BETTER ANTIARRHYTHMIC DRUGS ARE NEEDED

Atrial fibrillation increases the risk of stroke fivefold and accounts for 15% to 20% of all strokes.¹ It also increases the risk of heart failure. Drugs are the mainstay of therapy, but many antiarrhythmic drugs are not very effective and cause cardiac and extracardiac toxicity. Thus, the need for safe and effective new drugs.²

Much effort is going into the development of drugs that target specific ion channels or proteins expressed predominantly in atrial myocardium. The rationale is to avoid the unwanted effects of ionic currents on the ventricle and thus avoid ventricular proarrhythmic effects. At the same time, alternatives to the multiple channel blocker amiodarone, the mainstay of heart rhythm control therapy in atrial fibrillation, are being developed to retain the electrophysiologic efficacy of the mother compound but avoid its extracardiac toxicity.

RATE CONTROL VS RHYTHM CONTROL

In the acute care setting, heart rate control with atrioventricular nodal agents (beta-blockers, calcium channel blockers, and digitalis) is the preferred initial strategy in most hemodynamically stable patients presenting with new-onset atrial fibrillation.³

Since we lack an effective method for maintaining sinus rhythm without incurring significant adverse effects, rate control is also often chosen for chronic management of atrial fibrillation. This is particularly true for patients who have no symptoms or only minimal symptoms and in whom adequate rate control is easily attained. Indeed, results of large clinical trials suggest that rate control is satisfactory for many patients.

The main purpose of rate control is to control symptoms as opposed to merely lowering the ventricular rate. Effective rate control often prevents hemodynamic instability in patients with underlying heart disease who present acutely with atrial fibrillation. In patients with permanent atrial fibrillation, the RACE II study⁴ (Rate Control Efficacy in Permanent Atrial Fibrillation: a Comparison between Lenient Versus Strict Rate Control II), during a 3-year follow-up, showed that lenient rate control (resting heart rate < 110 beats per minute) is not inferior to strict rate control (resting heart rate < 80 beats per minute) in preventing major cardiovascular events (heart failure, stroke) or arrhythmic events such as syncope and sustained ventricular tachycardia.⁴

As a long-term strategy, rate control also prevents tachycardia-induced cardiomyopathy, reduces the risk of worsening of underlying heart failure, and can improve symptoms and quality of life.

Although maintenance of sinus rhythm is most likely associated with a survival benefit, heart rhythm control with antiarrhythmic drugs has not shown an advantage over rate control in overall or cardiovascular death rates, thromboembolic complications, or impact on heart failure. Indeed, a rhythm control strategy has been associated only with better exercise tolerance and, although less clear, with better quality of life.⁵

One possible explanation as to why a rhythm control strategy has not been shown to be superior to a rate control strategy is the side effects of the presently available drugs for rhythm control.

In a subgroup analysis of the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial,⁶ antiarrhythmic therapy was associated with a 49% increase in the mortality rate that offset the benefits of conversion and maintenance of sinus rhythm, which was associated with a 53% reduction in mortality rates.

The hope is that newer drugs with less toxicity may produce better outcomes for patients treated with rhythm control.

AN ANALOGUE OF AMIODARONE, WITHOUT THE IODINE

Dronedarone is a structurally modified version of amiodarone, the antiarrhythmic drug that has shown the greatest efficacy at maintaining sinus rhythm in patients with paroxysmal atrial fibrillation. Although historically amiodarone has been effective in maintaining sinus rhythm and has been used safely in patients with advanced heart failure, its use has been limited by cumulative and often irreversible extracardiac organ toxicity.

Dronedarone was designed to match amiodarone’s efficacy but with a better safety profile. An iodine radical makes up more than one-third of amiodarone’s molecular weight. The omission of iodine in dronedarone was intended to reduce the likelihood of toxic side effects.

Dronedarone is a benzofuran derivative pharmacologically related to amiodarone, with the addition of a methylsulfonamide group. This reduces lipophilicity and the propensity to cross the blood-brain barrier; over a 2-year period this drug has not been shown to have neurotoxic effects.⁷

Dronedarone has proved efficacious without toxic or proarrhythmic effects and has minimal side effects, but concerns remain regarding its use in advanced heart failure. To date, its adverse-event profile appears comparable to that of placebo. However, whether its efficacy and incidence of adverse effects are comparable to what has been reported in the literature may take time to assess.

DRONEDARONE’S PHARMACOLOGY

Dronedarone, like amiodarone, blocks multiple sodium and potassium ion channels. It also exerts an antiadrenergic effect by noncompetitive binding to beta-adrenergic receptors as well as by inhibiting an agonist-induced increase in adenylate cyclase activity.⁸ Compared with amiodarone, dronedarone is a more potent blocker of peak sodium current.

Dronedarone is largely metabolized by the hepatic enzyme cytochrome P450 3A4 isoform (CYP3A4). Only 6% of dronedarone is excreted renally; however, no trial has yet assessed dronedarone’s safety in patients with marked kidney dysfunction.⁸⁹

Dronedarone’s steady-state terminal elimination half-life is approximately 30 hours. When taken twice a day, it achieves steady-state concentrations in 5 to 7 days.

Dronedarone is available only for oral administration at 400 mg twice daily. Dose adjustment or titration is not recommended.

CLINICAL TRIALS OF DRONEDARONE

Dronedarone vs placebo

ATHENA (A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg bid for the Prevention of Cardiovascular Hospitalization or Death From any Cause in Patients With Atrial Fibrillation/Atrial Flutter)¹⁰ was a prospective, double-blind study to assess morbidity and death rates in 4,628 patients with atrial fibrillation or atrial flutter and at least one other cardiovascular risk factor.

EURIDIS and ADONIS. Two trials,¹¹ EURIDIS (European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm) and ADONIS (American-Australian Trial With Dronedarone in Atrial Fibrillation or Flutter Patients for the Maintenance of Sinus Rhythm), enrolled a total of more than 1,200 patients and showed that dronedarone 400 mg twice a day produced a significantly lower rate of recurrence of atrial fibrillation after electrical cardioversion compared with placebo.

Overall, treatment with dronedarone significantly reduced the risk of a first recurrence of atrial fibrillation by 22% (ADONIS) and 27.5% (EURIDIS) (Table 1).

ERATO (Efficacy and Safety of Dronedarone for the Control of Ventricular Rate During Atrial Fibrillation),¹² an additional phase III study, showed that dronedarone controlled the heart rate in patients with persistently accelerated ventricular rates despite concomitant standard therapy with a beta-blocker, digitalis, or a calcium-channel blocker. Dronedarone reduced the mean 24-hour heart rate by 11.7 beats per minute and the maximal exercise ventricular rate by 24.5 beats per minute at the 14th day.

ANDROMEDA (Anti-arrhythmic Trial With Dronedarone in Moderate to Severe CHF Evaluating Morbidity Decrease)¹³ was a study not of patients with atrial fibrillation but rather of patients with symptomatic congestive heart failure, a left ventricular ejection fraction of 35% or less, and recent hospitalization with new or worsening heart failure. The study was terminated early because of a higher rate of death with dronedarone¹³ (Table 1).

Dronedarone vs amiodarone

DIONYSOS (Efficacy and Safety of Dronedarone Versus Amiodarone for the Maintenance of Sinus Rhythm in Patients With Atrial Fibrillation)¹⁴ was a randomized double-blind trial. It evaluated the efficacy and safety of dronedarone (400 mg twice daily) or amiodarone (600 mg daily for 28 days, then 200 mg daily thereafter) for at least 6 months for the maintenance of sinus rhythm in patients with atrial fibrillation. It enrolled 504 patients with persistent atrial fibrillation; patients had not previously taken amiodarone. Dronedarone was less effective than amiodarone in maintaining sinus rhythm: the rate of recurrent atrial fibrillation was 63% with dronedarone and 42% with amiodarone. But dronedarone was associated with fewer adverse effects and less need for premature discontinuation of drug treatment at a mean follow-up of 7 months (Table 1).

WHERE DOES DRONEDARONE FIT IN ATRIAL FIBRILLATION MANAGEMENT?

Dronedarone is indicated in persistent or paroxysmal atrial fibrillation, based on the observed reduction of the rate of hospitalization. It is indicated for the maintenance of sinus rhythm and may be used in patients with persistent or paroxysmal atrial fibrillation and flutter who are in sinus rhythm or will be undergoing cardioversion soon after starting the drug. Dronedarone has no role in the acute management of atrial fibrillation, such as in cardioversion to sinus rhythm in the emergency department.

We do not have substantial evidence of the efficacy of dronedarone in patients with resistant atrial fibrillation, in whom multiple antiarrhythmics have failed to maintain sinus rhythm, and no published trial has used the inclusion criterion of treatment failure with other antiarrhythmic drugs.

The role of dronedarone in heart failure with preserved systolic function is unclear. Patients taking dronedarone are twice as likely as those taking amiodarone to have a recurrence of atrial fibrillation.

The main advantage of dronedarone is its lower adverse effect profile. However, this statement is based on only a few years of observation. If the patient has developed adverse effects with amiodarone, or if the clinician is concerned about the risk of serious adverse effects, dronedarone presents an alternative for those patients without heart failure or significant left ventricular dysfunction. One such group may be younger patients, because of concerns about the cumulative effects of amiodarone taken over a lifetime.

Dronedarone may represent an acceptable alternative to many of the current antiarrhythmic drugs. Based on the results of the Cardiac Arrhythmia Suppression Trial (CAST),¹⁵ class IC antiarrhythmics such as flecainide (Tambocor) are generally avoided in patients with prior myocardial infarction or with known or even suspected coronary artery disease. Similarly, sotalol (Betapace) is generally avoided in patients with marked left ventricular hypertrophy because of adverse effects.¹⁶ Dofetilide (Tikosyn) and often sotalol require hospitalization with telemetric monitoring for QTc prolongation and the risk of proarrhythmia with torsades de pointes. Dronedarone, however, generally can be safely started in the outpatient setting.

As when considering prescribing any antiarrhythmic, the clinician must assess the patient’s thromboembolic risk, since this risk persists with a rhythm control strategy.

There is substantial evidence from the ATHENA trial,¹⁰ in which 30% of the patients had coronary artery disease, that dronedarone is safe and effective in patients with coronary artery disease. Its use in patients who have undergone coronary artery bypass surgery remains to be defined.

WHEN SHOULD WE SWITCH PATIENTS TO DRONEDARONE?

Preliminary experience suggests that dronedarone, unlike most antiarrhythmic drugs, can be safely started about 48 hours after amiodarone is discontinued. Cumulative toxicity has not been noted with dronedarone. Caution should be exercised when switching if the patient has baseline bradycardia or QT interval prolongation. No algorithm has been developed for switching from other antiarrhythmic drugs to dronedarone.

CONTRAINDICATIONS TO DRONEDARONE

Dronedarone is contraindicated in:

• Patients with New York Heart Association (NYHA) class IV heart failure or NYHA class II or III heart failure with recent decompensation requiring hospitalization or referral to a specialized heart failure clinic
• Patients with second- or third-degree atrioventricular block or sick sinus syndrome (except when used in conjunction with a functioning pacemaker) or bradycardia (a heart rate < 50 beats per minute)
• Patients with a QTc interval of 500 ms or longer
• Patients with severe hepatic impairment
• Women who are pregnant, are attempting to become pregnant, or are breast-feeding
• Patients taking potent CYP3A inhibitors—antifungals like ketoconazole (Nizoral), itraconazole (Sporanox), or voriconazole (VFEND); macrolide antibiotics like telithromycin (Ketek) or clarithromycin (Biaxin); protease inhibitors; or other drugs that prolong the QT interval.

In patients with new or worsening heart failure, one should consider suspending or stopping dronedarone therapy.

DRONEDARONE’S ADVERSE EFFECTS

In trials to date, dronedarone has not shown evidence of proarrhythmia (tachyarrhythmia or bradyarrythmia), torsades de pointes, or amiodarone-like organ toxicity affecting the thyroid or the lungs. Recently, rare cases of severe hepatic injury were associated with dronedarone; therefore, periodic liver function testing is advised for patients taking dronedarone, especially during the first 6 months of therapy.

Dronedarone has been associated with higher rates of diarrhea, nausea, bradycardia, QT interval prolongation, and cutaneous rash compared with placebo. In DAFNE (Dronedarone Atrial Fibrillation Study After Electrical Cardioversion),¹⁷ 10.8% of patients taking dronedarone had to stop taking it because of adverse events. With 800 mg daily, the discontinuation rate was only 3.9%. The most common cause of drug discontinuation was gastrointestinal effects. Anecdotal reports suggest that the gastrointestinal side effects may be self-limited and may not always require discontinuation of the drug.

Serum creatinine levels increase by about 0.1 mg/dL after the start of treatment. This elevation occurs after 1 to 2 days, reaches a plateau after 7 days, and is reversible. The mechanism is thought to be that dronedarone partially inhibits tubular organic cation transporters, which in turn reduces renal creatinine clearance by about 18%, but with no evidence of an effect on glomerular filtration, renal plasma flow, or electrolyte exchanges.¹⁸ A limited increase in serum creatinine is, therefore, expected with dronedarone treatment, but this does not mean there is a decline in renal function.

DRONEDARONE AND POTENTIAL DRUG INTERACTIONS

Warfarin. Dronedarone does not increase the international normalized ratio when used with warfarin (Coumadin).

Verapamil, diltiazem. Dose reduction is required to avoid bradyarrhythmias with co-administration of moderate CYP3A4 inhibitors such as verapamil (Calan, Verelan) and diltiazem (Cardizem).

Simvastatin. Dronedarone increases levels of simvastatin (Zocor), a CYP3A4 substrate, two to four times, thus increasing the risk of statin-induced myopathy.

Digoxin. Dronedarone increases the serum digoxin concentration about 2.5 times, and this necessitates monitoring the digoxin level and possibly reducing the digoxin dose.¹³

Diuretics. Hypokalemia and hypomagnesemia may occur with concomitant administration of potassium-depleting diuretics. Potassium levels should be maintained in the normal range before and during administration of dronedarone.

Tacrolimus, sirolimus. Dronedarone may increase levels of tacrolimus (Prograf) or sirolimus (Rapamune) in posttransplantation patients. This requires dose monitoring and adjustment in concomitant therapy with these agents.

COST VARIES

The cost of dronedarone varies based on factors that include location. Dronedarone’s retail cost ranges from $3.20 to $4.00 per pill (approximately $7.20 per day). It is not available in generic form. It is presently covered by many health plans as a tier 2 drug, representing a $15 to $40 monthly copay.

MORE DATA NEEDED

Dronedarone represents the first in what may well be a number of new antiarrhythmic drugs for the treatment of patients with paroxysmal atrial fibrillation. Although less efficacious then amiodarone, dronedarone appears to be better tolerated and have less serious side effects. It is contraindicated in patients with severe systolic dysfunction and in those with recent heart failure decompensation. It appears safe in coronary artery disease and marked left ventricular hypertrophy, unlike flecainide, propafenone (Rythmol), and sotalol.

To further understand how dronedarone will fare against other antiarrhythmic drugs, more studies with longer follow-up are needed. These studies need to demonstrate superior tolerability of dronedarone, acceptable quality of life without unacceptable loss of efficacy, or a decrease in morbidity or mortality rates compared with amiodarone.

Dronedarone can be safely started in most patients on an outpatient basis. The risk of proarrhythmia with dronedarone appears to be very low.

Dronedarone (Multaq), approved by the US Food and Drug Administration in July 2009, is a congener of the antiarrhythmic drug amiodarone (Cordarone). Designed in the hope that it would be safer than amiodarone, its official indication is to lower the risk of hospitalization in patients with paroxysmal or persistent atrial fibrillation or atrial flutter. However, its precise role in the management of atrial fibrillation is yet to be defined. If dronedarone remains well tolerated, it may permit clinicians to pursue a rhythm control strategy more often. In this article, we present a progress report on this new agent.

BETTER ANTIARRHYTHMIC DRUGS ARE NEEDED

Atrial fibrillation increases the risk of stroke fivefold and accounts for 15% to 20% of all strokes.¹ It also increases the risk of heart failure. Drugs are the mainstay of therapy, but many antiarrhythmic drugs are not very effective and cause cardiac and extracardiac toxicity. Thus, the need for safe and effective new drugs.²

Much effort is going into the development of drugs that target specific ion channels or proteins expressed predominantly in atrial myocardium. The rationale is to avoid the unwanted effects of ionic currents on the ventricle and thus avoid ventricular proarrhythmic effects. At the same time, alternatives to the multiple channel blocker amiodarone, the mainstay of heart rhythm control therapy in atrial fibrillation, are being developed to retain the electrophysiologic efficacy of the mother compound but avoid its extracardiac toxicity.

RATE CONTROL VS RHYTHM CONTROL

In the acute care setting, heart rate control with atrioventricular nodal agents (beta-blockers, calcium channel blockers, and digitalis) is the preferred initial strategy in most hemodynamically stable patients presenting with new-onset atrial fibrillation.³

Since we lack an effective method for maintaining sinus rhythm without incurring significant adverse effects, rate control is also often chosen for chronic management of atrial fibrillation. This is particularly true for patients who have no symptoms or only minimal symptoms and in whom adequate rate control is easily attained. Indeed, results of large clinical trials suggest that rate control is satisfactory for many patients.

The main purpose of rate control is to control symptoms as opposed to merely lowering the ventricular rate. Effective rate control often prevents hemodynamic instability in patients with underlying heart disease who present acutely with atrial fibrillation. In patients with permanent atrial fibrillation, the RACE II study⁴ (Rate Control Efficacy in Permanent Atrial Fibrillation: a Comparison between Lenient Versus Strict Rate Control II), during a 3-year follow-up, showed that lenient rate control (resting heart rate < 110 beats per minute) is not inferior to strict rate control (resting heart rate < 80 beats per minute) in preventing major cardiovascular events (heart failure, stroke) or arrhythmic events such as syncope and sustained ventricular tachycardia.⁴

As a long-term strategy, rate control also prevents tachycardia-induced cardiomyopathy, reduces the risk of worsening of underlying heart failure, and can improve symptoms and quality of life.

Although maintenance of sinus rhythm is most likely associated with a survival benefit, heart rhythm control with antiarrhythmic drugs has not shown an advantage over rate control in overall or cardiovascular death rates, thromboembolic complications, or impact on heart failure. Indeed, a rhythm control strategy has been associated only with better exercise tolerance and, although less clear, with better quality of life.⁵

One possible explanation as to why a rhythm control strategy has not been shown to be superior to a rate control strategy is the side effects of the presently available drugs for rhythm control.

In a subgroup analysis of the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial,⁶ antiarrhythmic therapy was associated with a 49% increase in the mortality rate that offset the benefits of conversion and maintenance of sinus rhythm, which was associated with a 53% reduction in mortality rates.

The hope is that newer drugs with less toxicity may produce better outcomes for patients treated with rhythm control.

AN ANALOGUE OF AMIODARONE, WITHOUT THE IODINE

Dronedarone is a structurally modified version of amiodarone, the antiarrhythmic drug that has shown the greatest efficacy at maintaining sinus rhythm in patients with paroxysmal atrial fibrillation. Although historically amiodarone has been effective in maintaining sinus rhythm and has been used safely in patients with advanced heart failure, its use has been limited by cumulative and often irreversible extracardiac organ toxicity.

Dronedarone was designed to match amiodarone’s efficacy but with a better safety profile. An iodine radical makes up more than one-third of amiodarone’s molecular weight. The omission of iodine in dronedarone was intended to reduce the likelihood of toxic side effects.

Dronedarone is a benzofuran derivative pharmacologically related to amiodarone, with the addition of a methylsulfonamide group. This reduces lipophilicity and the propensity to cross the blood-brain barrier; over a 2-year period this drug has not been shown to have neurotoxic effects.⁷

Dronedarone has proved efficacious without toxic or proarrhythmic effects and has minimal side effects, but concerns remain regarding its use in advanced heart failure. To date, its adverse-event profile appears comparable to that of placebo. However, whether its efficacy and incidence of adverse effects are comparable to what has been reported in the literature may take time to assess.

DRONEDARONE’S PHARMACOLOGY

Dronedarone, like amiodarone, blocks multiple sodium and potassium ion channels. It also exerts an antiadrenergic effect by noncompetitive binding to beta-adrenergic receptors as well as by inhibiting an agonist-induced increase in adenylate cyclase activity.⁸ Compared with amiodarone, dronedarone is a more potent blocker of peak sodium current.

Dronedarone is largely metabolized by the hepatic enzyme cytochrome P450 3A4 isoform (CYP3A4). Only 6% of dronedarone is excreted renally; however, no trial has yet assessed dronedarone’s safety in patients with marked kidney dysfunction.⁸⁹

Dronedarone’s steady-state terminal elimination half-life is approximately 30 hours. When taken twice a day, it achieves steady-state concentrations in 5 to 7 days.

Dronedarone is available only for oral administration at 400 mg twice daily. Dose adjustment or titration is not recommended.

CLINICAL TRIALS OF DRONEDARONE

Dronedarone vs placebo

ATHENA (A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg bid for the Prevention of Cardiovascular Hospitalization or Death From any Cause in Patients With Atrial Fibrillation/Atrial Flutter)¹⁰ was a prospective, double-blind study to assess morbidity and death rates in 4,628 patients with atrial fibrillation or atrial flutter and at least one other cardiovascular risk factor.

EURIDIS and ADONIS. Two trials,¹¹ EURIDIS (European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm) and ADONIS (American-Australian Trial With Dronedarone in Atrial Fibrillation or Flutter Patients for the Maintenance of Sinus Rhythm), enrolled a total of more than 1,200 patients and showed that dronedarone 400 mg twice a day produced a significantly lower rate of recurrence of atrial fibrillation after electrical cardioversion compared with placebo.

Overall, treatment with dronedarone significantly reduced the risk of a first recurrence of atrial fibrillation by 22% (ADONIS) and 27.5% (EURIDIS) (Table 1).

ERATO (Efficacy and Safety of Dronedarone for the Control of Ventricular Rate During Atrial Fibrillation),¹² an additional phase III study, showed that dronedarone controlled the heart rate in patients with persistently accelerated ventricular rates despite concomitant standard therapy with a beta-blocker, digitalis, or a calcium-channel blocker. Dronedarone reduced the mean 24-hour heart rate by 11.7 beats per minute and the maximal exercise ventricular rate by 24.5 beats per minute at the 14th day.

ANDROMEDA (Anti-arrhythmic Trial With Dronedarone in Moderate to Severe CHF Evaluating Morbidity Decrease)¹³ was a study not of patients with atrial fibrillation but rather of patients with symptomatic congestive heart failure, a left ventricular ejection fraction of 35% or less, and recent hospitalization with new or worsening heart failure. The study was terminated early because of a higher rate of death with dronedarone¹³ (Table 1).

Dronedarone vs amiodarone

DIONYSOS (Efficacy and Safety of Dronedarone Versus Amiodarone for the Maintenance of Sinus Rhythm in Patients With Atrial Fibrillation)¹⁴ was a randomized double-blind trial. It evaluated the efficacy and safety of dronedarone (400 mg twice daily) or amiodarone (600 mg daily for 28 days, then 200 mg daily thereafter) for at least 6 months for the maintenance of sinus rhythm in patients with atrial fibrillation. It enrolled 504 patients with persistent atrial fibrillation; patients had not previously taken amiodarone. Dronedarone was less effective than amiodarone in maintaining sinus rhythm: the rate of recurrent atrial fibrillation was 63% with dronedarone and 42% with amiodarone. But dronedarone was associated with fewer adverse effects and less need for premature discontinuation of drug treatment at a mean follow-up of 7 months (Table 1).

WHERE DOES DRONEDARONE FIT IN ATRIAL FIBRILLATION MANAGEMENT?

Dronedarone is indicated in persistent or paroxysmal atrial fibrillation, based on the observed reduction of the rate of hospitalization. It is indicated for the maintenance of sinus rhythm and may be used in patients with persistent or paroxysmal atrial fibrillation and flutter who are in sinus rhythm or will be undergoing cardioversion soon after starting the drug. Dronedarone has no role in the acute management of atrial fibrillation, such as in cardioversion to sinus rhythm in the emergency department.

We do not have substantial evidence of the efficacy of dronedarone in patients with resistant atrial fibrillation, in whom multiple antiarrhythmics have failed to maintain sinus rhythm, and no published trial has used the inclusion criterion of treatment failure with other antiarrhythmic drugs.

The role of dronedarone in heart failure with preserved systolic function is unclear. Patients taking dronedarone are twice as likely as those taking amiodarone to have a recurrence of atrial fibrillation.

The main advantage of dronedarone is its lower adverse effect profile. However, this statement is based on only a few years of observation. If the patient has developed adverse effects with amiodarone, or if the clinician is concerned about the risk of serious adverse effects, dronedarone presents an alternative for those patients without heart failure or significant left ventricular dysfunction. One such group may be younger patients, because of concerns about the cumulative effects of amiodarone taken over a lifetime.

Dronedarone may represent an acceptable alternative to many of the current antiarrhythmic drugs. Based on the results of the Cardiac Arrhythmia Suppression Trial (CAST),¹⁵ class IC antiarrhythmics such as flecainide (Tambocor) are generally avoided in patients with prior myocardial infarction or with known or even suspected coronary artery disease. Similarly, sotalol (Betapace) is generally avoided in patients with marked left ventricular hypertrophy because of adverse effects.¹⁶ Dofetilide (Tikosyn) and often sotalol require hospitalization with telemetric monitoring for QTc prolongation and the risk of proarrhythmia with torsades de pointes. Dronedarone, however, generally can be safely started in the outpatient setting.

As when considering prescribing any antiarrhythmic, the clinician must assess the patient’s thromboembolic risk, since this risk persists with a rhythm control strategy.

There is substantial evidence from the ATHENA trial,¹⁰ in which 30% of the patients had coronary artery disease, that dronedarone is safe and effective in patients with coronary artery disease. Its use in patients who have undergone coronary artery bypass surgery remains to be defined.

WHEN SHOULD WE SWITCH PATIENTS TO DRONEDARONE?

Preliminary experience suggests that dronedarone, unlike most antiarrhythmic drugs, can be safely started about 48 hours after amiodarone is discontinued. Cumulative toxicity has not been noted with dronedarone. Caution should be exercised when switching if the patient has baseline bradycardia or QT interval prolongation. No algorithm has been developed for switching from other antiarrhythmic drugs to dronedarone.

CONTRAINDICATIONS TO DRONEDARONE

Dronedarone is contraindicated in:

• Patients with New York Heart Association (NYHA) class IV heart failure or NYHA class II or III heart failure with recent decompensation requiring hospitalization or referral to a specialized heart failure clinic
• Patients with second- or third-degree atrioventricular block or sick sinus syndrome (except when used in conjunction with a functioning pacemaker) or bradycardia (a heart rate < 50 beats per minute)
• Patients with a QTc interval of 500 ms or longer
• Patients with severe hepatic impairment
• Women who are pregnant, are attempting to become pregnant, or are breast-feeding
• Patients taking potent CYP3A inhibitors—antifungals like ketoconazole (Nizoral), itraconazole (Sporanox), or voriconazole (VFEND); macrolide antibiotics like telithromycin (Ketek) or clarithromycin (Biaxin); protease inhibitors; or other drugs that prolong the QT interval.

In patients with new or worsening heart failure, one should consider suspending or stopping dronedarone therapy.

DRONEDARONE’S ADVERSE EFFECTS

In trials to date, dronedarone has not shown evidence of proarrhythmia (tachyarrhythmia or bradyarrythmia), torsades de pointes, or amiodarone-like organ toxicity affecting the thyroid or the lungs. Recently, rare cases of severe hepatic injury were associated with dronedarone; therefore, periodic liver function testing is advised for patients taking dronedarone, especially during the first 6 months of therapy.

Dronedarone has been associated with higher rates of diarrhea, nausea, bradycardia, QT interval prolongation, and cutaneous rash compared with placebo. In DAFNE (Dronedarone Atrial Fibrillation Study After Electrical Cardioversion),¹⁷ 10.8% of patients taking dronedarone had to stop taking it because of adverse events. With 800 mg daily, the discontinuation rate was only 3.9%. The most common cause of drug discontinuation was gastrointestinal effects. Anecdotal reports suggest that the gastrointestinal side effects may be self-limited and may not always require discontinuation of the drug.

Serum creatinine levels increase by about 0.1 mg/dL after the start of treatment. This elevation occurs after 1 to 2 days, reaches a plateau after 7 days, and is reversible. The mechanism is thought to be that dronedarone partially inhibits tubular organic cation transporters, which in turn reduces renal creatinine clearance by about 18%, but with no evidence of an effect on glomerular filtration, renal plasma flow, or electrolyte exchanges.¹⁸ A limited increase in serum creatinine is, therefore, expected with dronedarone treatment, but this does not mean there is a decline in renal function.

DRONEDARONE AND POTENTIAL DRUG INTERACTIONS

Warfarin. Dronedarone does not increase the international normalized ratio when used with warfarin (Coumadin).

Verapamil, diltiazem. Dose reduction is required to avoid bradyarrhythmias with co-administration of moderate CYP3A4 inhibitors such as verapamil (Calan, Verelan) and diltiazem (Cardizem).

Simvastatin. Dronedarone increases levels of simvastatin (Zocor), a CYP3A4 substrate, two to four times, thus increasing the risk of statin-induced myopathy.

Digoxin. Dronedarone increases the serum digoxin concentration about 2.5 times, and this necessitates monitoring the digoxin level and possibly reducing the digoxin dose.¹³

Diuretics. Hypokalemia and hypomagnesemia may occur with concomitant administration of potassium-depleting diuretics. Potassium levels should be maintained in the normal range before and during administration of dronedarone.

Tacrolimus, sirolimus. Dronedarone may increase levels of tacrolimus (Prograf) or sirolimus (Rapamune) in posttransplantation patients. This requires dose monitoring and adjustment in concomitant therapy with these agents.

COST VARIES

The cost of dronedarone varies based on factors that include location. Dronedarone’s retail cost ranges from $3.20 to $4.00 per pill (approximately $7.20 per day). It is not available in generic form. It is presently covered by many health plans as a tier 2 drug, representing a $15 to $40 monthly copay.

MORE DATA NEEDED

Dronedarone represents the first in what may well be a number of new antiarrhythmic drugs for the treatment of patients with paroxysmal atrial fibrillation. Although less efficacious then amiodarone, dronedarone appears to be better tolerated and have less serious side effects. It is contraindicated in patients with severe systolic dysfunction and in those with recent heart failure decompensation. It appears safe in coronary artery disease and marked left ventricular hypertrophy, unlike flecainide, propafenone (Rythmol), and sotalol.

To further understand how dronedarone will fare against other antiarrhythmic drugs, more studies with longer follow-up are needed. These studies need to demonstrate superior tolerability of dronedarone, acceptable quality of life without unacceptable loss of efficacy, or a decrease in morbidity or mortality rates compared with amiodarone.

Dronedarone can be safely started in most patients on an outpatient basis. The risk of proarrhythmia with dronedarone appears to be very low.

Four months after undergoing laparoscopic cholecystectomy for symptomatic gallstones, an otherwise healthy 26-year-old woman begins to have episodes of epigastric and back pain similar to what she experienced before the surgery. The surgery was without complications, and her classic biliary colic disappeared afterward. Histologic evaluation of the surgical specimen revealed chronic cholecystitis with multiple small, mixed gallstones.

Now she describes a burning pain in her epigastrium and mid to upper back, starting about 30 minutes after a meal and lasting up to 4 hours. Sometimes it awakens her at night. She avoids eating for fear of inducing the pain. She has occasional chills but no fever, nausea, vomiting, jaundice, or changes in urine or stool color.

Three years ago she was diagnosed with a gastric ulcer induced by taking a nonsteroidal anti-inflammatory drug (NSAID). The ulcer was treated with a proton pump inhibitor for 1 month. She says the ulcer pain was dull and aching, different from her current pain.

Upper endoscopy 4 months ago (ie, before her laparoscopic cholecystectomy) showed no evidence of esophagitis or peptic ulcer disease.

Apart from her gallbladder operation, she has had no other surgery. According to the surgeon’s notes, intraoperative cholangiography was not performed, and no macroscopic changes of acute cholecystitis or difficult biliary anatomy were noted.

The patient does not smoke, does not drink alcohol, is not currently taking any medications, including NSAIDs or over-the-counter medications, and has not taken any recently. Her mother also had symptomatic gallstones requiring cholecystectomy.

On physical examination, only fever

On examination, her temperature is 101.2°F (38.4°C), blood pressure 117/80 mm Hg, heart rate 82 beats per minute, and blood oxygen saturation 99% on room air. Her weight is 138 lb (62.6 kg), height 5 feet 6 inches (168 cm).

There is no jaundice or pallor. Her heart and lung examinations are normal.

No costovertebral angle or spinal tenderness can be elicited.

Her laboratory values are shown in Table 1.

POSTCHOLECYSTECTOMY SYNDROME

1. After cholecystectomy, preoperative symptoms recur in what percentage of patients?

• 10% to 40%
• 50%
• 60%
• 80%

Postcholecystectomy syndrome—the recurrence of symptoms similar to those before the procedure—occurs in 10% to 40% of patients. The time to the onset of symptoms can range from 2 days to up to 25 years.^1–4 Women may be at higher risk, with symptoms recurring in 43% vs 28% in men.⁵

Postcholecystectomy syndrome can have a biliary or a nonbiliary cause. Biliary causes include strictures, retained calculi, dropped calculi, tumors, sphincter of Oddi dysfunction, and calculi in the cystic duct remnant. Nonbiliary causes include functional and organic disorders such as peptic ulcer disease, gastroesophageal reflux, pancreatic disease, hepatocellular disorders, coronary artery disease, irritable bowel syndrome, and intercostal neuritis.

WHAT IS THE NEXT STEP?

2. Which is the most appropriate next step in the workup of this patient?

• Ultrasonography of the right upper quadrant
• Magnetic resonance cholangiopancreatography (MRCP)
• Endoscopic retrograde cholangiopancreatography (ERCP)
• Observation and reassurance
• Review the operative record and consult with the surgeon

Although the patient is presenting with pain and fever, two features of the classic Charcot triad (pain, fever, jaundice) seen in cholangitis (infection of a bile duct), and although cholangitis almost confirms the diagnosis of common bile duct stones in a patient with gallstones (before or after cholecystectomy), other diagnoses to consider are bile duct injury, bile leak, and biloma.

Biloma can be detected with ultrasonography. Bile duct injuries are identified intraoperatively in up to 25% of patients. For those with an unrecognized injury, the clinical presentation is variable and depends on the type of injury. If a bile leak is present, patients present early, at a median of 3 days postoperatively. However, our patient presented with symptoms 4 months after her surgery. Patients with bile duct strictures without bile leak have a longer symptom-free interval and usually present with signs of biliary obstruction. Ultrasonography can then detect biliary dilatation.⁶

It would be very helpful to review the operative record and to talk to the surgeon to confirm that intraoperative cholangiography had not been done and to determine the level of difficulty of the surgery. (Intraoperative cholangiography involves the introduction of contrast dye into the biliary system by cannulation of the cystic duct or by direct injection into the common bile duct. An intraoperative cholangiogram is considered normal if the entire intrahepatic and extrahepatic biliary tree is seen to be filled with contrast.) A normal cholangiogram has a negative predictive value of 99.8% for the detection of ductal stones. Thus, a normal intraoperative cholangiogram can prevent unnecessary postoperative ECRP, since it almost always indicates a clean bile duct.⁷

Ultrasonography of the right upper quadrant has a low sensitivity (< 50%) for detecting common bile duct stones. However, it is highly operator-dependent, and it may be twice as sensitive if done by expert radiologists than by less experienced ones. Its limitations include poor visualization of the distal portion of the duct and low sensitivity in patients in whom the common bile duct is minimally dilated and also in patients with small stones. In most studies, however, it had a very high specificity—ie, greater than 95%.⁸

MRCP has a sensitivity of 82.6% and a specificity of 97.5% in detecting stones in the common bile duct.⁹ Therefore, normal results on abdominal ultrasonography and MRCP do not completely rule out stones.

Although this patient has a high pretest probability of having common bile duct stones, ERCP should be done only after a thorough review of the previous operative procedure.

Observation and reassurance are not appropriate in a patient with cholangitis, such as this patient, because waiting increases the risk of septicemia.

Review of the operative report and discussion with the surgeon confirm that the laparoscopic procedure was uneventful and that intraoperative cholangiography was not done.

Therefore, the patient undergoes ERCP. The major papilla is normal. Cholangiography reveals nondilated common bile and intrahepatic ducts, with faint filling defects in the mid to distal common bile duct. Endoscopic sphincterotomy is performed, and three small stones are extracted from the common bile duct. Repeat balloon-occlusion cholangiography is normal.

The patient tolerates the procedure well and resumes a normal diet and normal activities.

Her pain persists, prompting an emergency room visit

Five days after her ERCP procedure, however, the same burning epigastric pain returns. As before, the pain occurs after eating and does not occur with fasting. At this time, she has no fever or chills.

WHAT IS CAUSING HER PAIN?

3. Which is the most likely cause of her persistent pain?

• Acute pancreatitis after ERCP
• Peptic ulcer disease
• Sphincter of Oddi dysfunction
• Biliary stones

The most likely cause is persistent biliary stones. The common bile duct was recently explored and stones were removed, but she may still have stones in the intrahepatic ducts or in the cystic duct remnant, both of which were unopacified during the ERCP procedure, indicating that either the test was incomplete or a stone is obstructing the passage of contrast. Her persistent symptoms warrant repeating her liver function tests.

Acute pancreatitis is the most common and feared complication of ERCP, and it should be suspected in any patient who develops abdominal pain within 6 hours of the procedure. It is much less likely to develop after 12 hours, however. Risk factors for post-ERCP pancreatitis include patient factors (young age, female sex, history of recurrent pancreatitis), procedural factors (difficult cannulation, minor papilla sphincterotomy), and, less likely, operator-related factors.^10–13 In general, the more likely a patient is to have an abnormal and irregular common bile duct or pancreatic duct, the lower the risk of post-ERCP pancreatitis. The importance of operator-dependent factors is not yet clear.^10–13

Despite the postprandial pattern of our patient’s pain and her history of gastric ulcer, peptic ulcer disease is unlikely in view of a normal esophagogastroduodenoscopic examination done 4 months earlier, and since she has no recent exposure to NSAIDs.

Sphincter of Oddi dysfunction may explain her symptoms, but she recently underwent endoscopic sphincterotomy, which is regarded as the most definitive treatment.¹⁴

WHAT SHOULD BE DONE NEXT?

4. What would be the best next step in her management?

• Repeat ERCP
• MRCP
• Endoscopic ultrasonography
• Observation and reassurance

MRCP is the most appropriate next step, given her recurrent symptoms. Repeat ERCP is not appropriate, since there is no evidence of cholangitis, and since her liver function tests had completely normalized.

A recent systematic review of endoscopic ultrasonography and MRCP for diagnosing choledocholithiasis found both tests to be highly accurate, with no statistically significant differences in sensitivity or specificity between the two.¹⁵ However, MRCP has the advantage of being noninvasive and of being able to show intrahepatic stones.

Park et al,¹⁶ in a prospective study of 66 patients with primary intrahepatic stones, concluded that MRCP findings were comparable to those of percutaneous transhepatic cholangioscopy, the reference standard for locating intrahepatic stones. The sensitivity, specificity, and accuracy of MRCP for detecting and locating intrahepatic stones were high (97%, 99%, and 98%, respectively).¹⁶ However, after sphincterotomy, pneumobilia may create an appearance that can be mistaken for intraductal stones.

She undergoes MRCP

The patient continues to have pain, and she has lost 5 pounds because she is still avoiding eating. At this point, she is beginning to wonder if her symptoms are psychogenic, since all the test results have been normal.

ERCP, MRCP, ULTRASONOGRAPHY?

5. What would be the best next step?

• Reassurance
• Referral to a psychiatrist
• Referral to a pain management clinic
• Endoscopic ultrasonography
• Repeat ERCP

Endoscopic ultrasonography is needed to look for cystic duct stones. Although several tests have shown normal results, the patient’s pain continues as in the previous episodes, making stone disease the most likely cause.

Although no stones were seen on MRCP and ultrasonography, a detailed evaluation for stones in a cystic duct or retained gallbladder remnant was not done satisfactorily.

Reassurance and referral to a psychiatrist or pain management clinic are not appropriate, since an organic cause of her pain has not been completely ruled out.

Findings on endoscopic ultrasonography

Endoscopic ultrasonography is performed and reveals a large (7-mm) stone in the area of the cystic duct remnant or gallbladder remnant (Figure 3). The common bile duct is normal.

CAUSES OF RETAINED GALLBLADDER AND CYSTIC DUCT REMNANT

6. What may have predisposed this patient to a retained gallbladder or cystic duct remnant after her surgery?

• Laparoscopic cholecystectomy
• Not doing intraoperative cholangiography
• Cholecystectomy for acute cholecystitis
• All of the above

All of the above may have contributed.

Postcholecystectomy syndrome can pose a diagnostic and therapeutic challenge, as in our patient. Although it has been reported since the advent of the operation, it is more common after laparoscopic cholecystectomy than after open surgery. One possible cause is stones in a cystic duct remnant, ie, a stub longer than 1 cm.

During open cholecystectomy, the cystic duct is ligated and cut as close to the common bile duct as possible, leaving only a small remnant. In laparoscopic cholecystectomy, it is divided closer to the gallbladder to avoid iatrogenic injury to the common bile duct, leaving a longer remnant. A long cystic duct remnant can be prevented by accurately locating the junction of the gallbladder and the cystic duct during cholecystectomy and by routinely doing intraoperative cholangiography. The presence of stones in a cystic duct or retained gallbladder remnant is a rare cause of postcholecystectomy syndrome, and suspicion is required to make the diagnosis.^17–19

We should note that stones may also lurk in the short cystic duct remnant left after open cholecystectomy. In fact, the first case of cystic duct remnant, the so-called reformed gallbladder containing stones, was described in 1912 by Flörcken.²⁰

Intraoperative cholangiography was introduced in 1931 by Mirizzi,²¹ who recommended its routine use. Since the advent of laparoscopic cholecystectomy in 1988, the routine use of intraoperative cholangiography has been debated. Advocates point to its ability to detect unsuspected calculi and to delineate the biliary anatomy, thus reducing the risk of biliary duct injury.^7,22–25 Those who argue against its routine use emphasize the low reported rates of unsuspected stones in the common bile duct (2% to 3%), a longer operative time, the additional cost, and false-positive results that may lead to unnecessary common bile duct exploration. Another argument against its routine use is that most small ductal stones pass spontaneously without significant sequelae.^26–28 Surgeons who use intraoperative cholangiography only selectively use it in patients with unclear biliary anatomy and preoperative biochemical or radiologic evidence of choledocholithiasis.

Case continued: She undergoes repeat ERCP

IF STONES ARE DIFFICULT TO EXTRACT

7. If the cystic duct stone were not amenable to endoscopic extraction, what would be the best alternative?

• Extracorporeal shock-wave lithotripsy (ESWL)
• Endoscopic biliary laser lithotripsy
• Repeat laparoscopic cholecystectomy
• All of the above

All of the above are alternatives.

A symptomatic stone in a cystic duct remnant is uncommon and is mentioned in the literature only in case series and case reports.

ESWL is effective for treating bile duct calculi.²⁹ In a cohort of 239 patients with bile duct stones treated by ESWL, Benninger et al³⁰ concluded that endoscopy plus ESWL was a definitive treatment for all patients except one, who subsequently underwent cholecystectomy. Once fragmented, the stones are extracted endoscopically.

Another fragmentation technique that can be offered to patients with stones in the cystic duct that are difficult to extract is contact fragmentation with a holmium laser placed in a transpapillary position under visual guidance.¹⁷

Repeat cholecystectomy with removal of stones in the cystic duct remnant (and removal of retained gallbladder remnants and reduction of the cystic duct remnant) has good postoperative results.^17,18,31,32

After incomplete cholecystectomy, the cystic duct remnant and the Calot (cystohepatic) triangle are surrounded by inflamed scar tissue, and this was thought to make laparoscopic reoperation difficult.³³ However, with advances in surgical technique and increasing experience of surgeons, repeat cholecystectomy can be done laparoscopically. It has now been suggested that laparoscopic exploration to remove the gallbladder remnants is safe and feasible in such patients.^34,35

Discharge and follow-up

The patient is discharged home after the procedure. She is still free of symptoms 31 months later.

LESSONS LEARNED

Remnant cystic duct stones are uncommon

The estimated incidence of a retained calculus within the cystic duct remnant after cholecystectomy is less than 2.5%.^2,36 In a series of 322 patients who underwent repeat surgery because of postcholecystectomy syndrome, Rogy et al³⁶ found only 8 who had a stone in the cystic duct or gallbladder remnant, and in a series of 371 patients, Zhou el al² found 4 who had a stone in the cystic duct remnant.

Stones in the cystic duct remnant are difficult to diagnose

Diagnosing stones in surgical remnants of the cystic duct or gallbladder can be difficult. The sensitivity of abdominal ultrasonography in detecting cystic duct stones is low—only 27% in one study, with a specificity of 100% and an accuracy of 75%.³⁷ Ultrasonography may occasionally suggest cystic duct stones by showing an acoustic shadow in the anatomic region of the cystic duct. However, the results should be interpreted with caution.

Determining the accuracy of ERCP and MRCP in detecting cystic duct remnant stones is also difficult, as few cases have been reported and data may be conflicting. In a review of seven patients confirmed to have retained stones in a surgical remnant, Walsh et al¹⁷ found that ERCP correctly diagnosed the retained stone in only four out of six patients; MRCP was done in one patient, and it was read as normal.

In three cases of stones in a postsurgical gallbladder remnant, Hassan and Vilmann³⁸ reported that ERCP and MRCP failed to identify the gallbladder remnant in two out of three cases, likely because the remaining structures are small. The diagnosis was finally made by endoscopic ultrasonography, which the authors concluded was a valuable method to visualize a small gallbladder remnant with stones.

Greater suspicion is needed in patients with typical biliary colic after cholecystectomy

Retained gallbladder remnant is described in the literature as a latent complication. The main problem is not the remnant itself but the chance that it harbors retained stones, which can lead to dilatation and inflammation of the remnant.

The patient can develop symptoms of acute cholecystitis or even acute cholangitis if the stone migrates to the common bile duct. Symptoms can develop as early as 2 weeks or as late as 25 years after laparoscopic cholecystectomy.

Endoscopic ultrasonography may be the best way to look for these remnant stones and to evaluate the bile duct and pancreas. Therefore, it should be part of the diagnostic algorithm in the evaluation of postcholecystectomy pain.

Mixed results with ERCP for extracting cystic duct stones

In case reports of cystic duct calculi after cholecystectomy, ERCP by itself has had mixed results. This traditional means of removing stones may succeed, as in our case. However, the success rate depends largely on anatomic factors such as the position of the stone in the cystic duct, the degree of stone impaction, the diameter of the cystic duct, and the number of valves in the duct.¹⁷

Stones in the cystic duct that cannot be extracted with ERCP may benefit from fragmentation techniques in situ via holmium laser followed by endoscopic extraction.

Repeat cholecystectomy is generally advised for any residual gallbladder, and it can be done laparoscopically.

Four months after undergoing laparoscopic cholecystectomy for symptomatic gallstones, an otherwise healthy 26-year-old woman begins to have episodes of epigastric and back pain similar to what she experienced before the surgery. The surgery was without complications, and her classic biliary colic disappeared afterward. Histologic evaluation of the surgical specimen revealed chronic cholecystitis with multiple small, mixed gallstones.

Now she describes a burning pain in her epigastrium and mid to upper back, starting about 30 minutes after a meal and lasting up to 4 hours. Sometimes it awakens her at night. She avoids eating for fear of inducing the pain. She has occasional chills but no fever, nausea, vomiting, jaundice, or changes in urine or stool color.

Three years ago she was diagnosed with a gastric ulcer induced by taking a nonsteroidal anti-inflammatory drug (NSAID). The ulcer was treated with a proton pump inhibitor for 1 month. She says the ulcer pain was dull and aching, different from her current pain.

Upper endoscopy 4 months ago (ie, before her laparoscopic cholecystectomy) showed no evidence of esophagitis or peptic ulcer disease.

Apart from her gallbladder operation, she has had no other surgery. According to the surgeon’s notes, intraoperative cholangiography was not performed, and no macroscopic changes of acute cholecystitis or difficult biliary anatomy were noted.

The patient does not smoke, does not drink alcohol, is not currently taking any medications, including NSAIDs or over-the-counter medications, and has not taken any recently. Her mother also had symptomatic gallstones requiring cholecystectomy.

On physical examination, only fever

On examination, her temperature is 101.2°F (38.4°C), blood pressure 117/80 mm Hg, heart rate 82 beats per minute, and blood oxygen saturation 99% on room air. Her weight is 138 lb (62.6 kg), height 5 feet 6 inches (168 cm).

There is no jaundice or pallor. Her heart and lung examinations are normal.

No costovertebral angle or spinal tenderness can be elicited.

Her laboratory values are shown in Table 1.

POSTCHOLECYSTECTOMY SYNDROME

1. After cholecystectomy, preoperative symptoms recur in what percentage of patients?

• 10% to 40%
• 50%
• 60%
• 80%

Postcholecystectomy syndrome—the recurrence of symptoms similar to those before the procedure—occurs in 10% to 40% of patients. The time to the onset of symptoms can range from 2 days to up to 25 years.^1–4 Women may be at higher risk, with symptoms recurring in 43% vs 28% in men.⁵

Postcholecystectomy syndrome can have a biliary or a nonbiliary cause. Biliary causes include strictures, retained calculi, dropped calculi, tumors, sphincter of Oddi dysfunction, and calculi in the cystic duct remnant. Nonbiliary causes include functional and organic disorders such as peptic ulcer disease, gastroesophageal reflux, pancreatic disease, hepatocellular disorders, coronary artery disease, irritable bowel syndrome, and intercostal neuritis.

WHAT IS THE NEXT STEP?

2. Which is the most appropriate next step in the workup of this patient?

• Ultrasonography of the right upper quadrant
• Magnetic resonance cholangiopancreatography (MRCP)
• Endoscopic retrograde cholangiopancreatography (ERCP)
• Observation and reassurance
• Review the operative record and consult with the surgeon

Although the patient is presenting with pain and fever, two features of the classic Charcot triad (pain, fever, jaundice) seen in cholangitis (infection of a bile duct), and although cholangitis almost confirms the diagnosis of common bile duct stones in a patient with gallstones (before or after cholecystectomy), other diagnoses to consider are bile duct injury, bile leak, and biloma.

Biloma can be detected with ultrasonography. Bile duct injuries are identified intraoperatively in up to 25% of patients. For those with an unrecognized injury, the clinical presentation is variable and depends on the type of injury. If a bile leak is present, patients present early, at a median of 3 days postoperatively. However, our patient presented with symptoms 4 months after her surgery. Patients with bile duct strictures without bile leak have a longer symptom-free interval and usually present with signs of biliary obstruction. Ultrasonography can then detect biliary dilatation.⁶

It would be very helpful to review the operative record and to talk to the surgeon to confirm that intraoperative cholangiography had not been done and to determine the level of difficulty of the surgery. (Intraoperative cholangiography involves the introduction of contrast dye into the biliary system by cannulation of the cystic duct or by direct injection into the common bile duct. An intraoperative cholangiogram is considered normal if the entire intrahepatic and extrahepatic biliary tree is seen to be filled with contrast.) A normal cholangiogram has a negative predictive value of 99.8% for the detection of ductal stones. Thus, a normal intraoperative cholangiogram can prevent unnecessary postoperative ECRP, since it almost always indicates a clean bile duct.⁷

Ultrasonography of the right upper quadrant has a low sensitivity (< 50%) for detecting common bile duct stones. However, it is highly operator-dependent, and it may be twice as sensitive if done by expert radiologists than by less experienced ones. Its limitations include poor visualization of the distal portion of the duct and low sensitivity in patients in whom the common bile duct is minimally dilated and also in patients with small stones. In most studies, however, it had a very high specificity—ie, greater than 95%.⁸

MRCP has a sensitivity of 82.6% and a specificity of 97.5% in detecting stones in the common bile duct.⁹ Therefore, normal results on abdominal ultrasonography and MRCP do not completely rule out stones.

Although this patient has a high pretest probability of having common bile duct stones, ERCP should be done only after a thorough review of the previous operative procedure.

Observation and reassurance are not appropriate in a patient with cholangitis, such as this patient, because waiting increases the risk of septicemia.

Review of the operative report and discussion with the surgeon confirm that the laparoscopic procedure was uneventful and that intraoperative cholangiography was not done.

Therefore, the patient undergoes ERCP. The major papilla is normal. Cholangiography reveals nondilated common bile and intrahepatic ducts, with faint filling defects in the mid to distal common bile duct. Endoscopic sphincterotomy is performed, and three small stones are extracted from the common bile duct. Repeat balloon-occlusion cholangiography is normal.

The patient tolerates the procedure well and resumes a normal diet and normal activities.

Her pain persists, prompting an emergency room visit

Five days after her ERCP procedure, however, the same burning epigastric pain returns. As before, the pain occurs after eating and does not occur with fasting. At this time, she has no fever or chills.

WHAT IS CAUSING HER PAIN?

3. Which is the most likely cause of her persistent pain?

• Acute pancreatitis after ERCP
• Peptic ulcer disease
• Sphincter of Oddi dysfunction
• Biliary stones

The most likely cause is persistent biliary stones. The common bile duct was recently explored and stones were removed, but she may still have stones in the intrahepatic ducts or in the cystic duct remnant, both of which were unopacified during the ERCP procedure, indicating that either the test was incomplete or a stone is obstructing the passage of contrast. Her persistent symptoms warrant repeating her liver function tests.

Acute pancreatitis is the most common and feared complication of ERCP, and it should be suspected in any patient who develops abdominal pain within 6 hours of the procedure. It is much less likely to develop after 12 hours, however. Risk factors for post-ERCP pancreatitis include patient factors (young age, female sex, history of recurrent pancreatitis), procedural factors (difficult cannulation, minor papilla sphincterotomy), and, less likely, operator-related factors.^10–13 In general, the more likely a patient is to have an abnormal and irregular common bile duct or pancreatic duct, the lower the risk of post-ERCP pancreatitis. The importance of operator-dependent factors is not yet clear.^10–13

Despite the postprandial pattern of our patient’s pain and her history of gastric ulcer, peptic ulcer disease is unlikely in view of a normal esophagogastroduodenoscopic examination done 4 months earlier, and since she has no recent exposure to NSAIDs.

Sphincter of Oddi dysfunction may explain her symptoms, but she recently underwent endoscopic sphincterotomy, which is regarded as the most definitive treatment.¹⁴

WHAT SHOULD BE DONE NEXT?

4. What would be the best next step in her management?

• Repeat ERCP
• MRCP
• Endoscopic ultrasonography
• Observation and reassurance

MRCP is the most appropriate next step, given her recurrent symptoms. Repeat ERCP is not appropriate, since there is no evidence of cholangitis, and since her liver function tests had completely normalized.

A recent systematic review of endoscopic ultrasonography and MRCP for diagnosing choledocholithiasis found both tests to be highly accurate, with no statistically significant differences in sensitivity or specificity between the two.¹⁵ However, MRCP has the advantage of being noninvasive and of being able to show intrahepatic stones.

Park et al,¹⁶ in a prospective study of 66 patients with primary intrahepatic stones, concluded that MRCP findings were comparable to those of percutaneous transhepatic cholangioscopy, the reference standard for locating intrahepatic stones. The sensitivity, specificity, and accuracy of MRCP for detecting and locating intrahepatic stones were high (97%, 99%, and 98%, respectively).¹⁶ However, after sphincterotomy, pneumobilia may create an appearance that can be mistaken for intraductal stones.

She undergoes MRCP

The patient continues to have pain, and she has lost 5 pounds because she is still avoiding eating. At this point, she is beginning to wonder if her symptoms are psychogenic, since all the test results have been normal.

ERCP, MRCP, ULTRASONOGRAPHY?

5. What would be the best next step?

• Reassurance
• Referral to a psychiatrist
• Referral to a pain management clinic
• Endoscopic ultrasonography
• Repeat ERCP

Endoscopic ultrasonography is needed to look for cystic duct stones. Although several tests have shown normal results, the patient’s pain continues as in the previous episodes, making stone disease the most likely cause.

Although no stones were seen on MRCP and ultrasonography, a detailed evaluation for stones in a cystic duct or retained gallbladder remnant was not done satisfactorily.

Reassurance and referral to a psychiatrist or pain management clinic are not appropriate, since an organic cause of her pain has not been completely ruled out.

Findings on endoscopic ultrasonography

Endoscopic ultrasonography is performed and reveals a large (7-mm) stone in the area of the cystic duct remnant or gallbladder remnant (Figure 3). The common bile duct is normal.

CAUSES OF RETAINED GALLBLADDER AND CYSTIC DUCT REMNANT

6. What may have predisposed this patient to a retained gallbladder or cystic duct remnant after her surgery?

• Laparoscopic cholecystectomy
• Not doing intraoperative cholangiography
• Cholecystectomy for acute cholecystitis
• All of the above

All of the above may have contributed.

Postcholecystectomy syndrome can pose a diagnostic and therapeutic challenge, as in our patient. Although it has been reported since the advent of the operation, it is more common after laparoscopic cholecystectomy than after open surgery. One possible cause is stones in a cystic duct remnant, ie, a stub longer than 1 cm.

During open cholecystectomy, the cystic duct is ligated and cut as close to the common bile duct as possible, leaving only a small remnant. In laparoscopic cholecystectomy, it is divided closer to the gallbladder to avoid iatrogenic injury to the common bile duct, leaving a longer remnant. A long cystic duct remnant can be prevented by accurately locating the junction of the gallbladder and the cystic duct during cholecystectomy and by routinely doing intraoperative cholangiography. The presence of stones in a cystic duct or retained gallbladder remnant is a rare cause of postcholecystectomy syndrome, and suspicion is required to make the diagnosis.^17–19

We should note that stones may also lurk in the short cystic duct remnant left after open cholecystectomy. In fact, the first case of cystic duct remnant, the so-called reformed gallbladder containing stones, was described in 1912 by Flörcken.²⁰

Intraoperative cholangiography was introduced in 1931 by Mirizzi,²¹ who recommended its routine use. Since the advent of laparoscopic cholecystectomy in 1988, the routine use of intraoperative cholangiography has been debated. Advocates point to its ability to detect unsuspected calculi and to delineate the biliary anatomy, thus reducing the risk of biliary duct injury.^7,22–25 Those who argue against its routine use emphasize the low reported rates of unsuspected stones in the common bile duct (2% to 3%), a longer operative time, the additional cost, and false-positive results that may lead to unnecessary common bile duct exploration. Another argument against its routine use is that most small ductal stones pass spontaneously without significant sequelae.^26–28 Surgeons who use intraoperative cholangiography only selectively use it in patients with unclear biliary anatomy and preoperative biochemical or radiologic evidence of choledocholithiasis.

Case continued: She undergoes repeat ERCP

IF STONES ARE DIFFICULT TO EXTRACT

7. If the cystic duct stone were not amenable to endoscopic extraction, what would be the best alternative?

• Extracorporeal shock-wave lithotripsy (ESWL)
• Endoscopic biliary laser lithotripsy
• Repeat laparoscopic cholecystectomy
• All of the above

All of the above are alternatives.

A symptomatic stone in a cystic duct remnant is uncommon and is mentioned in the literature only in case series and case reports.

ESWL is effective for treating bile duct calculi.²⁹ In a cohort of 239 patients with bile duct stones treated by ESWL, Benninger et al³⁰ concluded that endoscopy plus ESWL was a definitive treatment for all patients except one, who subsequently underwent cholecystectomy. Once fragmented, the stones are extracted endoscopically.

Another fragmentation technique that can be offered to patients with stones in the cystic duct that are difficult to extract is contact fragmentation with a holmium laser placed in a transpapillary position under visual guidance.¹⁷

Repeat cholecystectomy with removal of stones in the cystic duct remnant (and removal of retained gallbladder remnants and reduction of the cystic duct remnant) has good postoperative results.^17,18,31,32

After incomplete cholecystectomy, the cystic duct remnant and the Calot (cystohepatic) triangle are surrounded by inflamed scar tissue, and this was thought to make laparoscopic reoperation difficult.³³ However, with advances in surgical technique and increasing experience of surgeons, repeat cholecystectomy can be done laparoscopically. It has now been suggested that laparoscopic exploration to remove the gallbladder remnants is safe and feasible in such patients.^34,35

Discharge and follow-up

The patient is discharged home after the procedure. She is still free of symptoms 31 months later.

LESSONS LEARNED

Remnant cystic duct stones are uncommon

The estimated incidence of a retained calculus within the cystic duct remnant after cholecystectomy is less than 2.5%.^2,36 In a series of 322 patients who underwent repeat surgery because of postcholecystectomy syndrome, Rogy et al³⁶ found only 8 who had a stone in the cystic duct or gallbladder remnant, and in a series of 371 patients, Zhou el al² found 4 who had a stone in the cystic duct remnant.

Stones in the cystic duct remnant are difficult to diagnose

Diagnosing stones in surgical remnants of the cystic duct or gallbladder can be difficult. The sensitivity of abdominal ultrasonography in detecting cystic duct stones is low—only 27% in one study, with a specificity of 100% and an accuracy of 75%.³⁷ Ultrasonography may occasionally suggest cystic duct stones by showing an acoustic shadow in the anatomic region of the cystic duct. However, the results should be interpreted with caution.

Determining the accuracy of ERCP and MRCP in detecting cystic duct remnant stones is also difficult, as few cases have been reported and data may be conflicting. In a review of seven patients confirmed to have retained stones in a surgical remnant, Walsh et al¹⁷ found that ERCP correctly diagnosed the retained stone in only four out of six patients; MRCP was done in one patient, and it was read as normal.

In three cases of stones in a postsurgical gallbladder remnant, Hassan and Vilmann³⁸ reported that ERCP and MRCP failed to identify the gallbladder remnant in two out of three cases, likely because the remaining structures are small. The diagnosis was finally made by endoscopic ultrasonography, which the authors concluded was a valuable method to visualize a small gallbladder remnant with stones.

Greater suspicion is needed in patients with typical biliary colic after cholecystectomy

Retained gallbladder remnant is described in the literature as a latent complication. The main problem is not the remnant itself but the chance that it harbors retained stones, which can lead to dilatation and inflammation of the remnant.

The patient can develop symptoms of acute cholecystitis or even acute cholangitis if the stone migrates to the common bile duct. Symptoms can develop as early as 2 weeks or as late as 25 years after laparoscopic cholecystectomy.

Endoscopic ultrasonography may be the best way to look for these remnant stones and to evaluate the bile duct and pancreas. Therefore, it should be part of the diagnostic algorithm in the evaluation of postcholecystectomy pain.

Mixed results with ERCP for extracting cystic duct stones

In case reports of cystic duct calculi after cholecystectomy, ERCP by itself has had mixed results. This traditional means of removing stones may succeed, as in our case. However, the success rate depends largely on anatomic factors such as the position of the stone in the cystic duct, the degree of stone impaction, the diameter of the cystic duct, and the number of valves in the duct.¹⁷

Stones in the cystic duct that cannot be extracted with ERCP may benefit from fragmentation techniques in situ via holmium laser followed by endoscopic extraction.

Repeat cholecystectomy is generally advised for any residual gallbladder, and it can be done laparoscopically.

Four months after undergoing laparoscopic cholecystectomy for symptomatic gallstones, an otherwise healthy 26-year-old woman begins to have episodes of epigastric and back pain similar to what she experienced before the surgery. The surgery was without complications, and her classic biliary colic disappeared afterward. Histologic evaluation of the surgical specimen revealed chronic cholecystitis with multiple small, mixed gallstones.

Now she describes a burning pain in her epigastrium and mid to upper back, starting about 30 minutes after a meal and lasting up to 4 hours. Sometimes it awakens her at night. She avoids eating for fear of inducing the pain. She has occasional chills but no fever, nausea, vomiting, jaundice, or changes in urine or stool color.

Three years ago she was diagnosed with a gastric ulcer induced by taking a nonsteroidal anti-inflammatory drug (NSAID). The ulcer was treated with a proton pump inhibitor for 1 month. She says the ulcer pain was dull and aching, different from her current pain.

Upper endoscopy 4 months ago (ie, before her laparoscopic cholecystectomy) showed no evidence of esophagitis or peptic ulcer disease.

Apart from her gallbladder operation, she has had no other surgery. According to the surgeon’s notes, intraoperative cholangiography was not performed, and no macroscopic changes of acute cholecystitis or difficult biliary anatomy were noted.

The patient does not smoke, does not drink alcohol, is not currently taking any medications, including NSAIDs or over-the-counter medications, and has not taken any recently. Her mother also had symptomatic gallstones requiring cholecystectomy.

On physical examination, only fever

On examination, her temperature is 101.2°F (38.4°C), blood pressure 117/80 mm Hg, heart rate 82 beats per minute, and blood oxygen saturation 99% on room air. Her weight is 138 lb (62.6 kg), height 5 feet 6 inches (168 cm).

There is no jaundice or pallor. Her heart and lung examinations are normal.

No costovertebral angle or spinal tenderness can be elicited.

Her laboratory values are shown in Table 1.

POSTCHOLECYSTECTOMY SYNDROME

1. After cholecystectomy, preoperative symptoms recur in what percentage of patients?

• 10% to 40%
• 50%
• 60%
• 80%

Postcholecystectomy syndrome—the recurrence of symptoms similar to those before the procedure—occurs in 10% to 40% of patients. The time to the onset of symptoms can range from 2 days to up to 25 years.^1–4 Women may be at higher risk, with symptoms recurring in 43% vs 28% in men.⁵

Postcholecystectomy syndrome can have a biliary or a nonbiliary cause. Biliary causes include strictures, retained calculi, dropped calculi, tumors, sphincter of Oddi dysfunction, and calculi in the cystic duct remnant. Nonbiliary causes include functional and organic disorders such as peptic ulcer disease, gastroesophageal reflux, pancreatic disease, hepatocellular disorders, coronary artery disease, irritable bowel syndrome, and intercostal neuritis.

WHAT IS THE NEXT STEP?

2. Which is the most appropriate next step in the workup of this patient?

• Ultrasonography of the right upper quadrant
• Magnetic resonance cholangiopancreatography (MRCP)
• Endoscopic retrograde cholangiopancreatography (ERCP)
• Observation and reassurance
• Review the operative record and consult with the surgeon

Although the patient is presenting with pain and fever, two features of the classic Charcot triad (pain, fever, jaundice) seen in cholangitis (infection of a bile duct), and although cholangitis almost confirms the diagnosis of common bile duct stones in a patient with gallstones (before or after cholecystectomy), other diagnoses to consider are bile duct injury, bile leak, and biloma.

Biloma can be detected with ultrasonography. Bile duct injuries are identified intraoperatively in up to 25% of patients. For those with an unrecognized injury, the clinical presentation is variable and depends on the type of injury. If a bile leak is present, patients present early, at a median of 3 days postoperatively. However, our patient presented with symptoms 4 months after her surgery. Patients with bile duct strictures without bile leak have a longer symptom-free interval and usually present with signs of biliary obstruction. Ultrasonography can then detect biliary dilatation.⁶

It would be very helpful to review the operative record and to talk to the surgeon to confirm that intraoperative cholangiography had not been done and to determine the level of difficulty of the surgery. (Intraoperative cholangiography involves the introduction of contrast dye into the biliary system by cannulation of the cystic duct or by direct injection into the common bile duct. An intraoperative cholangiogram is considered normal if the entire intrahepatic and extrahepatic biliary tree is seen to be filled with contrast.) A normal cholangiogram has a negative predictive value of 99.8% for the detection of ductal stones. Thus, a normal intraoperative cholangiogram can prevent unnecessary postoperative ECRP, since it almost always indicates a clean bile duct.⁷

Ultrasonography of the right upper quadrant has a low sensitivity (< 50%) for detecting common bile duct stones. However, it is highly operator-dependent, and it may be twice as sensitive if done by expert radiologists than by less experienced ones. Its limitations include poor visualization of the distal portion of the duct and low sensitivity in patients in whom the common bile duct is minimally dilated and also in patients with small stones. In most studies, however, it had a very high specificity—ie, greater than 95%.⁸

MRCP has a sensitivity of 82.6% and a specificity of 97.5% in detecting stones in the common bile duct.⁹ Therefore, normal results on abdominal ultrasonography and MRCP do not completely rule out stones.

Although this patient has a high pretest probability of having common bile duct stones, ERCP should be done only after a thorough review of the previous operative procedure.

Observation and reassurance are not appropriate in a patient with cholangitis, such as this patient, because waiting increases the risk of septicemia.

Review of the operative report and discussion with the surgeon confirm that the laparoscopic procedure was uneventful and that intraoperative cholangiography was not done.

Therefore, the patient undergoes ERCP. The major papilla is normal. Cholangiography reveals nondilated common bile and intrahepatic ducts, with faint filling defects in the mid to distal common bile duct. Endoscopic sphincterotomy is performed, and three small stones are extracted from the common bile duct. Repeat balloon-occlusion cholangiography is normal.

The patient tolerates the procedure well and resumes a normal diet and normal activities.

Her pain persists, prompting an emergency room visit

Five days after her ERCP procedure, however, the same burning epigastric pain returns. As before, the pain occurs after eating and does not occur with fasting. At this time, she has no fever or chills.

WHAT IS CAUSING HER PAIN?

3. Which is the most likely cause of her persistent pain?

• Acute pancreatitis after ERCP
• Peptic ulcer disease
• Sphincter of Oddi dysfunction
• Biliary stones

The most likely cause is persistent biliary stones. The common bile duct was recently explored and stones were removed, but she may still have stones in the intrahepatic ducts or in the cystic duct remnant, both of which were unopacified during the ERCP procedure, indicating that either the test was incomplete or a stone is obstructing the passage of contrast. Her persistent symptoms warrant repeating her liver function tests.

Acute pancreatitis is the most common and feared complication of ERCP, and it should be suspected in any patient who develops abdominal pain within 6 hours of the procedure. It is much less likely to develop after 12 hours, however. Risk factors for post-ERCP pancreatitis include patient factors (young age, female sex, history of recurrent pancreatitis), procedural factors (difficult cannulation, minor papilla sphincterotomy), and, less likely, operator-related factors.^10–13 In general, the more likely a patient is to have an abnormal and irregular common bile duct or pancreatic duct, the lower the risk of post-ERCP pancreatitis. The importance of operator-dependent factors is not yet clear.^10–13

Despite the postprandial pattern of our patient’s pain and her history of gastric ulcer, peptic ulcer disease is unlikely in view of a normal esophagogastroduodenoscopic examination done 4 months earlier, and since she has no recent exposure to NSAIDs.

Sphincter of Oddi dysfunction may explain her symptoms, but she recently underwent endoscopic sphincterotomy, which is regarded as the most definitive treatment.¹⁴

WHAT SHOULD BE DONE NEXT?

4. What would be the best next step in her management?

• Repeat ERCP
• MRCP
• Endoscopic ultrasonography
• Observation and reassurance

MRCP is the most appropriate next step, given her recurrent symptoms. Repeat ERCP is not appropriate, since there is no evidence of cholangitis, and since her liver function tests had completely normalized.

A recent systematic review of endoscopic ultrasonography and MRCP for diagnosing choledocholithiasis found both tests to be highly accurate, with no statistically significant differences in sensitivity or specificity between the two.¹⁵ However, MRCP has the advantage of being noninvasive and of being able to show intrahepatic stones.

Park et al,¹⁶ in a prospective study of 66 patients with primary intrahepatic stones, concluded that MRCP findings were comparable to those of percutaneous transhepatic cholangioscopy, the reference standard for locating intrahepatic stones. The sensitivity, specificity, and accuracy of MRCP for detecting and locating intrahepatic stones were high (97%, 99%, and 98%, respectively).¹⁶ However, after sphincterotomy, pneumobilia may create an appearance that can be mistaken for intraductal stones.

She undergoes MRCP

The patient continues to have pain, and she has lost 5 pounds because she is still avoiding eating. At this point, she is beginning to wonder if her symptoms are psychogenic, since all the test results have been normal.

ERCP, MRCP, ULTRASONOGRAPHY?

5. What would be the best next step?

• Reassurance
• Referral to a psychiatrist
• Referral to a pain management clinic
• Endoscopic ultrasonography
• Repeat ERCP

Endoscopic ultrasonography is needed to look for cystic duct stones. Although several tests have shown normal results, the patient’s pain continues as in the previous episodes, making stone disease the most likely cause.

Although no stones were seen on MRCP and ultrasonography, a detailed evaluation for stones in a cystic duct or retained gallbladder remnant was not done satisfactorily.

Reassurance and referral to a psychiatrist or pain management clinic are not appropriate, since an organic cause of her pain has not been completely ruled out.

Findings on endoscopic ultrasonography

Endoscopic ultrasonography is performed and reveals a large (7-mm) stone in the area of the cystic duct remnant or gallbladder remnant (Figure 3). The common bile duct is normal.

CAUSES OF RETAINED GALLBLADDER AND CYSTIC DUCT REMNANT

6. What may have predisposed this patient to a retained gallbladder or cystic duct remnant after her surgery?

• Laparoscopic cholecystectomy
• Not doing intraoperative cholangiography
• Cholecystectomy for acute cholecystitis
• All of the above

All of the above may have contributed.

Postcholecystectomy syndrome can pose a diagnostic and therapeutic challenge, as in our patient. Although it has been reported since the advent of the operation, it is more common after laparoscopic cholecystectomy than after open surgery. One possible cause is stones in a cystic duct remnant, ie, a stub longer than 1 cm.

During open cholecystectomy, the cystic duct is ligated and cut as close to the common bile duct as possible, leaving only a small remnant. In laparoscopic cholecystectomy, it is divided closer to the gallbladder to avoid iatrogenic injury to the common bile duct, leaving a longer remnant. A long cystic duct remnant can be prevented by accurately locating the junction of the gallbladder and the cystic duct during cholecystectomy and by routinely doing intraoperative cholangiography. The presence of stones in a cystic duct or retained gallbladder remnant is a rare cause of postcholecystectomy syndrome, and suspicion is required to make the diagnosis.^17–19

We should note that stones may also lurk in the short cystic duct remnant left after open cholecystectomy. In fact, the first case of cystic duct remnant, the so-called reformed gallbladder containing stones, was described in 1912 by Flörcken.²⁰

Intraoperative cholangiography was introduced in 1931 by Mirizzi,²¹ who recommended its routine use. Since the advent of laparoscopic cholecystectomy in 1988, the routine use of intraoperative cholangiography has been debated. Advocates point to its ability to detect unsuspected calculi and to delineate the biliary anatomy, thus reducing the risk of biliary duct injury.^7,22–25 Those who argue against its routine use emphasize the low reported rates of unsuspected stones in the common bile duct (2% to 3%), a longer operative time, the additional cost, and false-positive results that may lead to unnecessary common bile duct exploration. Another argument against its routine use is that most small ductal stones pass spontaneously without significant sequelae.^26–28 Surgeons who use intraoperative cholangiography only selectively use it in patients with unclear biliary anatomy and preoperative biochemical or radiologic evidence of choledocholithiasis.

Case continued: She undergoes repeat ERCP

IF STONES ARE DIFFICULT TO EXTRACT

7. If the cystic duct stone were not amenable to endoscopic extraction, what would be the best alternative?

• Extracorporeal shock-wave lithotripsy (ESWL)
• Endoscopic biliary laser lithotripsy
• Repeat laparoscopic cholecystectomy
• All of the above

All of the above are alternatives.

A symptomatic stone in a cystic duct remnant is uncommon and is mentioned in the literature only in case series and case reports.

ESWL is effective for treating bile duct calculi.²⁹ In a cohort of 239 patients with bile duct stones treated by ESWL, Benninger et al³⁰ concluded that endoscopy plus ESWL was a definitive treatment for all patients except one, who subsequently underwent cholecystectomy. Once fragmented, the stones are extracted endoscopically.

Another fragmentation technique that can be offered to patients with stones in the cystic duct that are difficult to extract is contact fragmentation with a holmium laser placed in a transpapillary position under visual guidance.¹⁷

Repeat cholecystectomy with removal of stones in the cystic duct remnant (and removal of retained gallbladder remnants and reduction of the cystic duct remnant) has good postoperative results.^17,18,31,32

After incomplete cholecystectomy, the cystic duct remnant and the Calot (cystohepatic) triangle are surrounded by inflamed scar tissue, and this was thought to make laparoscopic reoperation difficult.³³ However, with advances in surgical technique and increasing experience of surgeons, repeat cholecystectomy can be done laparoscopically. It has now been suggested that laparoscopic exploration to remove the gallbladder remnants is safe and feasible in such patients.^34,35

Discharge and follow-up

The patient is discharged home after the procedure. She is still free of symptoms 31 months later.

LESSONS LEARNED

Remnant cystic duct stones are uncommon

The estimated incidence of a retained calculus within the cystic duct remnant after cholecystectomy is less than 2.5%.^2,36 In a series of 322 patients who underwent repeat surgery because of postcholecystectomy syndrome, Rogy et al³⁶ found only 8 who had a stone in the cystic duct or gallbladder remnant, and in a series of 371 patients, Zhou el al² found 4 who had a stone in the cystic duct remnant.

Stones in the cystic duct remnant are difficult to diagnose

Diagnosing stones in surgical remnants of the cystic duct or gallbladder can be difficult. The sensitivity of abdominal ultrasonography in detecting cystic duct stones is low—only 27% in one study, with a specificity of 100% and an accuracy of 75%.³⁷ Ultrasonography may occasionally suggest cystic duct stones by showing an acoustic shadow in the anatomic region of the cystic duct. However, the results should be interpreted with caution.

Determining the accuracy of ERCP and MRCP in detecting cystic duct remnant stones is also difficult, as few cases have been reported and data may be conflicting. In a review of seven patients confirmed to have retained stones in a surgical remnant, Walsh et al¹⁷ found that ERCP correctly diagnosed the retained stone in only four out of six patients; MRCP was done in one patient, and it was read as normal.

In three cases of stones in a postsurgical gallbladder remnant, Hassan and Vilmann³⁸ reported that ERCP and MRCP failed to identify the gallbladder remnant in two out of three cases, likely because the remaining structures are small. The diagnosis was finally made by endoscopic ultrasonography, which the authors concluded was a valuable method to visualize a small gallbladder remnant with stones.

Greater suspicion is needed in patients with typical biliary colic after cholecystectomy

Retained gallbladder remnant is described in the literature as a latent complication. The main problem is not the remnant itself but the chance that it harbors retained stones, which can lead to dilatation and inflammation of the remnant.

The patient can develop symptoms of acute cholecystitis or even acute cholangitis if the stone migrates to the common bile duct. Symptoms can develop as early as 2 weeks or as late as 25 years after laparoscopic cholecystectomy.

Endoscopic ultrasonography may be the best way to look for these remnant stones and to evaluate the bile duct and pancreas. Therefore, it should be part of the diagnostic algorithm in the evaluation of postcholecystectomy pain.

Mixed results with ERCP for extracting cystic duct stones

In case reports of cystic duct calculi after cholecystectomy, ERCP by itself has had mixed results. This traditional means of removing stones may succeed, as in our case. However, the success rate depends largely on anatomic factors such as the position of the stone in the cystic duct, the degree of stone impaction, the diameter of the cystic duct, and the number of valves in the duct.¹⁷

Stones in the cystic duct that cannot be extracted with ERCP may benefit from fragmentation techniques in situ via holmium laser followed by endoscopic extraction.

Repeat cholecystectomy is generally advised for any residual gallbladder, and it can be done laparoscopically.

She denies any history of itching, insect bites, exposure to new medications or jewelry, allergies, recent change in medications, travel, or intravenous drug abuse.

Q: Which is the most likely diagnosis?

• Allergic contact dermatitis
• Xerosis
• Dermatotillomania
• Folliculitis
• Infestation (scabies)

A: Dermatotillomania, ie, pathologic skin picking, is the correct diagnosis. On further questioning, the patient reveals that the wounds have been self-inflicted over many years, starting in her adolescence. The wounds are located only in areas she can reach. She admits that social and emotional stressors had made the condition significantly worse and that lately she had lost control of her skin-picking. She denies nail-biting, trichotillomania, or obsessive-compulsive behavior.

As for the other possible diagnoses:

Allergic contact dermatitis occurs when contact with a particular substance elicits a hypersensitivity reaction. This reaction is of the delayed type (type IV). The affected individual can develop skin erythema and swelling with vesicles that are intensely pruritic at the contact site. The erythema may become evident hours after exposure, or not until weeks later, which can make the diagnosis difficult at times.

Our patient’s lesions were not pruritic, and she denied recent exposure to allergens.

Xerosis. Xerotic (dry) skin is usually rough, with fine scales and fissures. Xerosis can affect people of all ages and is often more intense during the winter. It affects mainly the arms, legs, and hands. Patients note pruritus, which can be treated with liberal use of emollients and tepid water baths.

Our patient’s lesions were scarred, hyperpigmented, and nonpruritic.

Folliculitis is a superficial infection of the hair follicle that presents as an erythematous pustule on the extremities, buttocks, or scalp. The pustule can be tender to palpation and can progress to an abscess that requires incision and drainage and intravenous antibiotics. A moist environment and poor hygiene are predisposing factors. Staphylococcus aureus is the culprit in most cases.

Our patient’s lesions were on the chest and upper back, where hair follicles were sparse or absent, and there was no erythema or tenderness.

Scabies is a skin infestation with Sarcoptes scabiei mites, which burrow in the skin and cause intense pruritus, especially at night. Scabies usually affects the sides and webs of the fingers and skin folds. Sexual contact is a common way of transmission; however, transmission can also occur by sharing beds and towels.

Patients with dermatotillomania lack intense pruritus, and skin-picking occurs during the day, while the patient is awake.

SELF-INFLICTED WOUNDS

Pathologic skin-picking, neurotic excoriation, excoriated acne, or dermatotillomania results from scratching, picking, gouging, or squeezing of one’s skin via teeth, fingernails, tweezers, or other objects.^1–3 Lesions are usually found on skin that the patient can easily reach, such as the face, chest, upper and lower extremities, and upper back.⁴

The prevalence of pathologic skin-picking is estimated at 2% in dermatology patients.⁵ The overall prevalence of psychiatric disorders in all dermatology outpatients is estimated at 30% to 40%. Women outnumber men with this disorder.⁶

Dermatotillomania is thought to be on the spectrum of obsessive-compulsive disorder, in which patients exhibit impulses and compulsions.⁵ It starts in childhood or early adulthood, with an average lifetime duration of 21 years.⁷ It is usually associated with anxiety, depression, obsessive-compulsive traits, eating disorders, body dysmorphic disorders, or hypochondriasis. Psychosocial stress is the main trigger. Patients report feelings of tension and stress before picking and relief while picking; there is no suicidal ideation.⁸

Treatments are both pharmacologic and behavioral.⁹ Cognitive behavioral therapy and habit reversal therapy have each been successful when used alone.⁸ In addition, several case reports¹⁰ and double-blind studies^11,12 have shown that treatment with a selective serotonin-reuptake inhibitor (SSRI) can reduce pathologic skin-picking.^13,14 However, SSRIs have also been reported to induce or aggravate this behavior in patients with underlying mild skin-picking and a family history of skin-picking.¹⁵ Thus, it is pertinent to extract a detailed history from the patient before prescribing an SSRI.

We referred our patient for behavioral therapy and prescribed fluoxetine (Prozac) 20 mg daily. She showed improvement in symptoms in 4 weeks and has since stopped skin-picking completely.

She denies any history of itching, insect bites, exposure to new medications or jewelry, allergies, recent change in medications, travel, or intravenous drug abuse.

Q: Which is the most likely diagnosis?

• Allergic contact dermatitis
• Xerosis
• Dermatotillomania
• Folliculitis
• Infestation (scabies)

A: Dermatotillomania, ie, pathologic skin picking, is the correct diagnosis. On further questioning, the patient reveals that the wounds have been self-inflicted over many years, starting in her adolescence. The wounds are located only in areas she can reach. She admits that social and emotional stressors had made the condition significantly worse and that lately she had lost control of her skin-picking. She denies nail-biting, trichotillomania, or obsessive-compulsive behavior.

As for the other possible diagnoses:

Allergic contact dermatitis occurs when contact with a particular substance elicits a hypersensitivity reaction. This reaction is of the delayed type (type IV). The affected individual can develop skin erythema and swelling with vesicles that are intensely pruritic at the contact site. The erythema may become evident hours after exposure, or not until weeks later, which can make the diagnosis difficult at times.

Our patient’s lesions were not pruritic, and she denied recent exposure to allergens.

Xerosis. Xerotic (dry) skin is usually rough, with fine scales and fissures. Xerosis can affect people of all ages and is often more intense during the winter. It affects mainly the arms, legs, and hands. Patients note pruritus, which can be treated with liberal use of emollients and tepid water baths.

Our patient’s lesions were scarred, hyperpigmented, and nonpruritic.

Folliculitis is a superficial infection of the hair follicle that presents as an erythematous pustule on the extremities, buttocks, or scalp. The pustule can be tender to palpation and can progress to an abscess that requires incision and drainage and intravenous antibiotics. A moist environment and poor hygiene are predisposing factors. Staphylococcus aureus is the culprit in most cases.

Our patient’s lesions were on the chest and upper back, where hair follicles were sparse or absent, and there was no erythema or tenderness.

Scabies is a skin infestation with Sarcoptes scabiei mites, which burrow in the skin and cause intense pruritus, especially at night. Scabies usually affects the sides and webs of the fingers and skin folds. Sexual contact is a common way of transmission; however, transmission can also occur by sharing beds and towels.

Patients with dermatotillomania lack intense pruritus, and skin-picking occurs during the day, while the patient is awake.

SELF-INFLICTED WOUNDS

Pathologic skin-picking, neurotic excoriation, excoriated acne, or dermatotillomania results from scratching, picking, gouging, or squeezing of one’s skin via teeth, fingernails, tweezers, or other objects.^1–3 Lesions are usually found on skin that the patient can easily reach, such as the face, chest, upper and lower extremities, and upper back.⁴

The prevalence of pathologic skin-picking is estimated at 2% in dermatology patients.⁵ The overall prevalence of psychiatric disorders in all dermatology outpatients is estimated at 30% to 40%. Women outnumber men with this disorder.⁶

Dermatotillomania is thought to be on the spectrum of obsessive-compulsive disorder, in which patients exhibit impulses and compulsions.⁵ It starts in childhood or early adulthood, with an average lifetime duration of 21 years.⁷ It is usually associated with anxiety, depression, obsessive-compulsive traits, eating disorders, body dysmorphic disorders, or hypochondriasis. Psychosocial stress is the main trigger. Patients report feelings of tension and stress before picking and relief while picking; there is no suicidal ideation.⁸

Treatments are both pharmacologic and behavioral.⁹ Cognitive behavioral therapy and habit reversal therapy have each been successful when used alone.⁸ In addition, several case reports¹⁰ and double-blind studies^11,12 have shown that treatment with a selective serotonin-reuptake inhibitor (SSRI) can reduce pathologic skin-picking.^13,14 However, SSRIs have also been reported to induce or aggravate this behavior in patients with underlying mild skin-picking and a family history of skin-picking.¹⁵ Thus, it is pertinent to extract a detailed history from the patient before prescribing an SSRI.

We referred our patient for behavioral therapy and prescribed fluoxetine (Prozac) 20 mg daily. She showed improvement in symptoms in 4 weeks and has since stopped skin-picking completely.