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Journal of Pain and Symptom Management 1
Palliative Care Rounds
Takotsubo Cardiomyopathy Secondary in Part to Cancer-Related Pain Crisis: A Case Report Stephen B. Singh, MD, CCFP, Cert Pall Med, and Ingrid A. Harle, BSc, MD, FRCS(C), CCFP, FCFP Palliative Care Medicine Program, Queen’s University, Kingston, Ontario, Canada
Introduction In the palliative care setting, patients often present with pain crises. However, potential cardiac complications of pain crises are rarely seen or discussed. One potential cardiac complication is Takotsubo cardiomyopathy (TC).1,2 If unrecognized or ignored, TC can cause an acute increase in suffering and mortality in this patient population. This case review examines the events preceding a presentation of TC in a patient with a prolonged pain crisis secondary to an underlying cancer diagnosis, who was admitted to the palliative care service of an acute care hospital. The case report serves to educate palliative medicine and oncology colleagues about this particular cardiac complication of pain crises. A review of the literature did not reveal any prior case reports of cancer-related pain crisis (without associated chemotherapy, radiation therapy, or opioid withdrawal) as a precipitating factor for the development of TC.
Case Description The patient was a 59-year-old West Indian woman who was a retired nurse. She was initially diagnosed with right upper lobe non-small cell
Address correspondence to: Stephen B. Singh, MD, CCFP, Cert Pall Med, Palliative Care Medicine Program, Queen’s University, 34 Barrie Street, Kingston, Ontario, K7L 3J7, Canada. E-mail: [email protected] Accepted for publication: September 1, 2013. Ó 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.
lung cancer (Stage 1B) in 2006 and treated with a right upper lobectomy followed by four cycles of adjuvant cisplatin and vinorelbine chemotherapy. In 2009, she developed new bilateral renal and unilateral adrenal metastases, with retroperitoneal lymphadenopathy. Several lines of chemotherapy were administered over the subsequent two years, but her disease continued to progress. She was initially started on cisplatin and gemcitabine (three cycles), followed by erlotinib. The latter was stopped after three weeks because of the development of rash and fever as part of a drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. Several months later, she was treated with six cycles of pemetrexed chemotherapy. Around this time, the patient developed thrombosis of the renal vein and inferior vena cava and was placed on lifelong dalteparin. The patient began seeing the palliative care team in early 2011 for the management of pain. She also was seen by radiation oncology for low back pain secondary to bone metastases and was treated with 2000 cGy in five fractions with palliative intent. One month later, she was found to have a right ischial tuberosity metastasis and received 800 cGy in one fraction of radiation to assist with pain management. She developed a compression fracture of L2, but orthopedic surgery did not recommend any surgical intervention. The patient received six weeks of gefitinib, which was discontinued approximately three weeks before presentation to hospital because of disease progression. She simultaneously received 800 cGy in one fraction to the right pelvis with palliative intent, which did not provide 0885-3924/$ - see front matter http://dx.doi.org/10.1016/j.jpainsymman.2013.09.002
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effective pain relief. Finally, she received a single injection of denosumab, a monoclonal antibody, approximately two weeks before presentation to hospital. The patient lived at home with her husband (substitute decision maker) and one daughter, with support from other family members in the vicinity. Other than what was mentioned previously, the patient’s medical history included mild chronic renal failure (baseline creatinine, 145 micromol/L) and gastroesophageal reflux disease. There was no history of coronary artery disease, heart failure, hypertension, diabetes mellitus, pheochromocytoma, smoking, alcohol intake, or recreational drug use. She had no family history of malignancy or cardiac conditions. Her medications at home included oral controlled release of hydromorphone 15 mg every 12 hours, hydromorphone 4 mg orally every two hours as needed for pain, nortriptyline, ondansetron, metoclopramide, calcium, vitamin D, and subcutaneous dalteparin. Her only documented allergy was to erlotinib, which previously caused a drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome as mentioned previously. She presented to an acute tertiary care center in the summer of 2011 with a pain crisis andsigns and symptoms of opioid toxicity, approximately three weeks after her last chemotherapy
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and radiation therapy and two weeks after the injection of denosumab. The baseline pain in her right ischium had increased over a period of days to include bilateral hips and lower back. She denied any saddle anesthesia, stool incontinence, or urinary retention. Her Palliative Performance Scale score had decreased from 60% to 40% in a matter of days. Signs of opioid toxicity included confusion and myoclonus. Significant findings on physical examination revealed an elevated blood pressure of 170/105, decreased power in the hips bilaterally, absent ankle reflexes, and normal rectal tone. The remainder of the physical examination was within normal limits. She was admitted to the palliative care inpatient service, and the opioid was rotated from oral hydromorphone to an intravenous (IV) infusion of fentanyl at a 50% dose reduction because of her opioid toxicity. Hydralazine was initiated to manage her elevated blood pressure. This patient’s previously expressed wishes included no attempts at cardiopulmonary resuscitation, and this was reconfirmed at the time of hospital admission. Her goals of care included investigation and management of any reversible causes of pain and confusion, plus optimizing symptom control. On the first day after admission, this patient developed a sudden increase in dyspnea and
Fig. 1. This electrocardiogram shows ST elevation in V2-V5 in our patient. Cardiac catheterization failed to find any coronary lesions.
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new onset anterior chest pain. She was found to be in acute congestive heart failure, with electrocardiogram (EKG) findings suspicious for an anterior ST-segment elevation myocardial infarction (Fig. 1). On discussion with the patient and her family, she clearly expressed the wish to have this acute event investigated and treated if possible. The cardiology service was consulted emergently. A bedside echocardiogram (Fig. 2) revealed signs of left ventricular apical ballooning without signs of overload or right ventricular failure, and there were no signs of pericardial effusion or tamponade. The left ventricular ejection fraction was 35%. An initial troponin I level was elevated at 3.2 mg/L (normal range 0e0.06). The patient underwent an urgent cardiac catheterization, which revealed normal coronary arteries with no signs of stenosis. Hence, a diagnosis of TC was made. The patient was transferred to the intensive care unit (ICU) for management with IV furosemide, IV nitrate infusion, oral metoprolol, oral spironolactone, and bilateral positive airway pressure. A decision was made to not monitor any cardiac enzymes as it would not affect the management of this patient. Over the ensuing days, the patient’s cardiac condition demonstrated clinical improvement with these supportive measures. Her oxygen requirements gradually decreased to the point where she required only low-flow oxygen by nasal prongs. She was successfully weaned off the IV nitrate and furosemide infusions. She was transferred from the ICU to the oncology floor under the palliative care service. Dyspnea
3
significantly improved throughout her hospitalization. A repeat echocardiogram at this time was not performed as the results would not have changed the current management. Unfortunately, the patient suffered additional complications in hospital unrelated to her TC, including an impending spinal cord compression from the metastatic disease to the thoracic spine, which necessitated a course of dexamethasone and five fractions of radiation therapy. After three weeks of hospitalization, the patient’s pain control was optimized on a continuous infusion of IV fentanyl administered by a continuous ambulatory delivery device (CADD) at a rate of 35 mg/hour, with a bolus dose of 45 mg every 30 minutes as needed for pain. Pain management was significantly improved and symptoms of opioid neurotoxicity had resolved. Her Palliative Performance Scale score on discharge was 30%. She was discharged home on an IV fentanyl infusion by continuous ambulatory delivery device ([CADD] as described previously), oral metoprolol, spironolactone, dexamethasone, metoclopramide, subcutaneous dalteparin, and home oxygen. Follow-up was to be provided by the home care nurses and a palliative care physician in her local community. The patient wished to receive endof-life care in her home surrounded by loved ones. Her prognosis was estimated to be within weeks to months of discharge. Although there was no further contact with our tertiary palliative care team after discharge, we were available for phone consultation with her local palliative care physician.
Comment
Fig. 2. This bedside echocardiogram shows a dilated akinetic ballooning of the apex along with a hyperdynamic base.
With the assistance of the Canadian Library of Family Medicine, a literature review of TC was undertaken. Ovid MEDLINEÒ MeSH search terms pertaining to TC and its synonyms (including transient apical ballooning syndrome, apical ballooning cardiomyopathy, stress-induced cardiomyopathy, GebrochenesHerz-Syndrom, stress cardiomyopathy, and broken heart syndrome) were used, with search dates from January 2007 to October 2011, yielding almost 70 articles describing the pathophysiology, etiology, diagnosis, and management of TC. Only English language
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articles were examined. A search of ‘‘cancer’’ or ‘‘neoplasms,’’ which automatically explodes all subtypes to include all cancer articles regardless of type, combined with TC and its synonyms, revealed four articles, concentrating on either chemotherapy- or radiation therapyinduced TC. A search for articles on ‘‘withdrawal,’’ combined with terms pertaining to TC, revealed eight articles. These articles discussed withdrawals from medications (including opioids) and alcohol as etiological factors leading to TC. Articles on pheochromocytoma catecholamine-induced pain were excluded as per the Mayo Clinic criteria for TC.2 No articles were found based on a search combining ‘‘pain crisis’’ or ‘‘pain crises’’ with TC and its synonyms, from the period of 1948 to October 2011. Oral consent to present this case report was obtained from the patient and her family, which was documented in the patient’s chart. Approval was obtained from the Queen’s University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board. TC, also known as stress-induced cardiomyopathy, transient apical ballooning, or ‘‘broken heart syndrome,’’ was first described in 1990 by Sato et al.2e4 The differential diagnosis includes acute coronary syndrome (ACS), angina pectoris, myocarditis, aortic dissection, cardiac tamponade, and Boerhaave syndrome.5 It is associated with a sudden nonischemic left ventricular dysfunction in which the left ventricle resembles a Japanese octopus trap (from which the condition gets its name), with a narrow neck and wide base.2 Patients may present with symptoms resembling an ACS, despite the absence of obstructive coronary artery disease on angiography. They can sometimes present with life-threatening and distressing flash pulmonary edema, cardiogenic shock, and ventricular arrhythmias.4,6 The prevalence of TC among patients with a suspected myocardial infarction is 0.7% e2.5%.4 Ninety-one percent of TC patients are women between the ages of 62 and 76 years.3,6 Treatment is typically supportive in nature, and TC usually resolves on average over 18 days (range 9e53 days).1 In-hospital mortality is estimated at 2%.4 Looking at all-cause mortality, the four year survival of patients with TC is no different than that in patients of an age- and sex-matched population.5
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However, the recurrence rate of TC within the four year period is 11.4%.6 Several theories exist regarding the etiology of this disorder, including coronary artery vasospasm and left ventricular outflow tract obstruction.4 The most accepted theory is that TC is catecholamine induced, from a combination of emotional and/or physical pain.4 In the literature, 44% of stressful events that initiate TC are emotional in nature, and 36% are physical.7 The criteria for diagnosing TC, as per the updated Mayo Clinic criteria,2 are as follows: 1. Transient abnormality of left ventricular contraction with akinesia of the apex and hyperkinesis of the base. Typically, the coronary arteries lack findings of stenosis, but the presence of stenosis does not exclude the possibility of TC. 2. Other combinations of akinesia and hyperkinesis are permitted, known as either ‘‘atypical’’ or ‘‘inverted’’ TC. 3. The motion abnormalities resolve in four to eight weeks, although in some patients, they can take up to one year to resolve. 4. The most common EKG changes are STsegment elevations in the chest leads V1eV6, with T-wave inversions beginning to form in all leads. 5. Pheochromocytoma, myocarditis, and physical stressors such as head trauma, seizures, and stroke should be excluded. The case presented definitely meets the updated Mayo Clinic criteria for TC. The patient developed sudden apical ballooning as seen on a bedside echocardiogram, with an ejection fraction of 35%. No baseline ejection fraction was known as the patient did not have any cardiac history or known risk factors for cardiac disease. EKG findings were suspicious for an ST-segment elevation myocardial infarction, but cardiac catheterization failed to find any coronary lesions. From a cardiac standpoint, the patient improved clinically with supportive management. Initial treatment was in the ICU with bilateral positive airway pressure, IV furosemide, and nitrates. On discharge from hospital, the patient continued on oral metoprolol and spironolactone for her TC. Cardiology recommended that she could return in six months time for a repeat echocardiogram. The plan at that time would be to discontinue metoprolol and spironolactone if her motion
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abnormalities had completely resolved on reassessment. However, the patient declined to return to hospital as it was her wish to remain at home until death. Although we did not specifically rule out the possibility of pheochromocytoma (such as through measurements of urinary and plasma fractionated metanephrines and catecholamines), the fact that the patient lacked any previous episodes of hypertension, combined with a lack of headache, diaphoresis, or tachycardia, made such a diagnosis less likely. As a palliative care physician, it is important to remember that TC mimics an ACS and initially one cannot differentiate the two. The decision of whether to further investigate a suspected ACS depends greatly on the patient’s goals of care. Factors to bring into a discussion about goals of care could include the state of the patient’s disease, the patient’s functional status and rate of decline, and current and projected quality of life. In the case of our patient, she had a rapid decrease in functional status over a period of days and wished to have investigations and treatment for potential reversible conditions. She wished to maximize her chance of being discharged to be able to die at home surrounded by her family. She understood that this acute cardiac event had the potential of ending her life sooner than her underlying disease and, therefore, wanted us to attempt to reverse it. Only after this discussion had taken place, did we proceed with further investigation and treatment. Generally, the treatment of TC, once diagnosed, is supportive and empirical in nature.6 Cardiology and internal medicine specialists should be involved from the outset. The literature supports management of TC with beta blockers, given the likely mechanism of catecholamine-induced myocardial stunning, but there is no available evidence of benefit in preventing recurrence of TC.6 Hemodynamically stable patients also may benefit from an angiotensin-converting enzyme inhibitor, although again there is no clear evidence for long-term benefit in prevention of recurrence.6 The literature advises the administration of anxiolytic agents, especially if a physical or emotional stressor is expected to continue long term.6 For the treatment of congestive heart failure, diuretics have been shown to be effective.6 The treatment of
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hemodynamically unstable patients is beyond the scope of this case report, and specialist consultation would be highly recommended. Although experimental data suggest that estrogen therapy may have a role in the prevention of TC in postmenopausal women, no randomized controlled studies have been performed, and thus, no recommendations can be made.6 As mentioned in the literature search, no prior case reports describing cancer-related pain crisis as a contributory precipitating etiology for the development of TC could be found. Two case reports have described the development of TC after administration of 5-fluorouracil (5-FU) chemotherapy. The first case occurred two weeks after administration of 5-FU,8 and the second case occurred 24 hours after administration.9 Two cases also have been reported after combrestatin-based chemotherapy used in the treatment of anaplastic thyroid cancer, one occurring 18 hours after administration and the second occurring immediately after chemotherapy administration.10 Our patient never received 5-FU or combrestatin-based chemotherapy regimens. However, it is possible that the administration of a chemotherapy agent and monoclonal antibody, three and two weeks, respectively, before presentation, may have contributed to the development of TC in our patient. One case report has described radiation therapy-induced TC, 12 days after administration, although the radiation in that case report was directed at the patient’s chest,11 which could have contributed to an increased risk of developing TC if the heart was in the radiation field. This differs from our patient, who received radiation therapy to the hip three weeks before presentation. TC also has been reported after alcohol withdrawal,12 metoprolol withdrawal,13 poisoning with cardiotoxic drugs,14 and postoperatively.15 The unifying theory among these case reports is that TC is catecholamine induced. This case report lends further credence to that theory as cancer-induced pain crisis is a state of high circulating catecholamines. One possible contributing factor to our patient developing TC was the opioid rotation with dose reduction because of opioid toxicity. At the time of opioid rotation, her pain was not well controlled. In one case of opioid withdrawal,16 a patient developed TC after being
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unable to obtain prescription opioids for one week. The baseline dose of opioid was not clearly stated in the article. This case in the literature is different from our case, in that it describes a patient who developed a seizure and required intubation. Another case described in the literature was one of methadone withdrawal,17 in which a patient on 120 mg/day of methadone was reportedly given naltrexone to stop alcohol consumption and developed an acute opioid withdrawal syndrome. Our patient was not given an opioid antagonist, but, because of opioid toxicity, was rotated to a different opioid with a dose reduction, as per clinical practice guidelines.
2. Sinning Ch, Keller T, Abegunewardene N, et al. Tako-Tsubo syndrome: dying of a broken heart? Clin Res Cardiol 2010;99:771e780.
Conclusion
7. Pernicova I, Garg S, Bourantas CV, Alamgir F, Hoye A. Takotsubo cardiomyopathy: a review of the literature. Angiology 2010;61:166e173.
Pain crises are often seen in patients with cancer, but potential cardiac complications of these crises are rarely considered or discussed. TC is a diagnosis that should be considered in patients presenting with signs and symptoms mimicking a myocardial infarction, especially after a period of physical and/or emotional stress. Early recognition and management of this condition can help prevent morbidity and mortality and can contribute to improvement in patients’ quality of life. Based on the literature search we conducted, to our knowledge, this case report is the first to attribute a cancer-related pain crisis as a contributory precipitating event for the development of TC. This report also lends further evidence to the leading theory that TC is catecholamine induced in nature.
Disclosures and Acknowledgments The authors thank the The Canadian Library of Family Medicine for assistance with the literature search, Dr. A. Johri from Queen’s University for assistance with interpretation of the echocardiogram, and the Queen’s University Palliative Care Medicine Program. Dr. S. Singh also thanks Dr. J. Tang for her ongoing support. This work received no funding, and the authors have no conflicts of interest to declare.
References 1. Bielecka-Dabrowa A, Mikhailidis DP, Hannam S, et al. Takotsubo cardiomyopathydthe current state of knowledge. Int J Cardiol 2010;142:120e125.
3. Tarkin JM, Khetyar M, Kaski JC. Management of Tako-tsubo syndrome. Cardiovasc Drugs Ther 2008; 22:71e77. 4. Nef HM, M€ ollmann H, Akashi YJ, Hamm CW. Mechanisms of stress (Takotsubo) cardiomyopathy. Nat Rev Cardiol 2010;7:187e193. 5. Tomich EB, Luerssen E, Kang CS. Takotsubo cardiomyopathy [Internet]. New York: Medscape, 2012. Available from http://emedicine.medscape. com/article/1513631-differential. Accessed April 9, 2012. 6. Palecek T, Kuchynka P, Linhart A. Treatment of Takotsubo cardiomyopathy. Curr Pharm Des 2010; 16:2905e2909.
8. Gianni M, Dentali F, Lonn E. 5 fluorouracilinduced apical ballooning syndrome: a case report. Blood Coagul Fibrinolysis 2009;20:306e308. 9. Basselin C, Fontanges T, Descotes J, et al. 5-Fluorouracil-induced Tako-Tsubo-like syndrome. Pharmacotherapy 2011;31:226. 10. Bhakta S, Flick SM, Cooney MM, et al. Myocardial stunning following combined modality combretastatin-based chemotherapy: two case reports and review of the literature. Clin Cardiol 2009;32:E80eE84. 11. Modi S, Baig W. Radiotherapy-induced Takotsubo cardiomyopathy. Clin Oncol (R Coll Radiol) 2009;21:361e362. 12. Alexandre J, Benouda L, Champ-Rigot L, Labombarda F. Takotsubo cardiomyopathy triggered by alcohol withdrawal. Drug Alcohol Rev 2011;30:434e437. 13. Jefic D, Koul D, Boguszewski A, Martini W. Transient left ventricular apical ballooning syndrome caused by abrupt metoprolol withdrawal. Int J Cardiol 2008;131:e35ee37. 14. Hantson P, Beauloye C. Myocardial metabolism in toxin-induced heart failure and therapeutic implications. Clin Toxicol (Phila) 2012;50:166e171. 15. Daly MJ, Dixon LJ. Takotsubo cardiomyopathy in two preoperative patients with pain. Anesth Analg 2010;110:708e711. 16. Yousuf MA, Adjei S, Kinder B. A 58-year-old woman with ST-segment elevation, seizures, and altered mental status in the setting of opiate withdrawal. Chest 2009;135:1098e1101. 17. Lemesle F, Lemesle F, Nicola W, Pierre JonvilleB era A. First case of stress cardiomyopathy as a result of methadone withdrawal secondary to drug-drug interaction. Am J Emerg Med 2010;28:387.
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Journal of Pain and Symptom Management 1
Palliative Care Rounds
Takotsubo Cardiomyopathy Secondary in Part to Cancer-Related Pain Crisis: A Case Report Stephen B. Singh, MD, CCFP, Cert Pall Med, and Ingrid A. Harle, BSc, MD, FRCS(C), CCFP, FCFP Palliative Care Medicine Program, Queen’s University, Kingston, Ontario, Canada
Introduction In the palliative care setting, patients often present with pain crises. However, potential cardiac complications of pain crises are rarely seen or discussed. One potential cardiac complication is Takotsubo cardiomyopathy (TC).1,2 If unrecognized or ignored, TC can cause an acute increase in suffering and mortality in this patient population. This case review examines the events preceding a presentation of TC in a patient with a prolonged pain crisis secondary to an underlying cancer diagnosis, who was admitted to the palliative care service of an acute care hospital. The case report serves to educate palliative medicine and oncology colleagues about this particular cardiac complication of pain crises. A review of the literature did not reveal any prior case reports of cancer-related pain crisis (without associated chemotherapy, radiation therapy, or opioid withdrawal) as a precipitating factor for the development of TC.
Case Description The patient was a 59-year-old West Indian woman who was a retired nurse. She was initially diagnosed with right upper lobe non-small cell
Address correspondence to: Stephen B. Singh, MD, CCFP, Cert Pall Med, Palliative Care Medicine Program, Queen’s University, 34 Barrie Street, Kingston, Ontario, K7L 3J7, Canada. E-mail: [email protected] Accepted for publication: September 1, 2013. Ó 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.
lung cancer (Stage 1B) in 2006 and treated with a right upper lobectomy followed by four cycles of adjuvant cisplatin and vinorelbine chemotherapy. In 2009, she developed new bilateral renal and unilateral adrenal metastases, with retroperitoneal lymphadenopathy. Several lines of chemotherapy were administered over the subsequent two years, but her disease continued to progress. She was initially started on cisplatin and gemcitabine (three cycles), followed by erlotinib. The latter was stopped after three weeks because of the development of rash and fever as part of a drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. Several months later, she was treated with six cycles of pemetrexed chemotherapy. Around this time, the patient developed thrombosis of the renal vein and inferior vena cava and was placed on lifelong dalteparin. The patient began seeing the palliative care team in early 2011 for the management of pain. She also was seen by radiation oncology for low back pain secondary to bone metastases and was treated with 2000 cGy in five fractions with palliative intent. One month later, she was found to have a right ischial tuberosity metastasis and received 800 cGy in one fraction of radiation to assist with pain management. She developed a compression fracture of L2, but orthopedic surgery did not recommend any surgical intervention. The patient received six weeks of gefitinib, which was discontinued approximately three weeks before presentation to hospital because of disease progression. She simultaneously received 800 cGy in one fraction to the right pelvis with palliative intent, which did not provide 0885-3924/$ - see front matter http://dx.doi.org/10.1016/j.jpainsymman.2013.09.002
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effective pain relief. Finally, she received a single injection of denosumab, a monoclonal antibody, approximately two weeks before presentation to hospital. The patient lived at home with her husband (substitute decision maker) and one daughter, with support from other family members in the vicinity. Other than what was mentioned previously, the patient’s medical history included mild chronic renal failure (baseline creatinine, 145 micromol/L) and gastroesophageal reflux disease. There was no history of coronary artery disease, heart failure, hypertension, diabetes mellitus, pheochromocytoma, smoking, alcohol intake, or recreational drug use. She had no family history of malignancy or cardiac conditions. Her medications at home included oral controlled release of hydromorphone 15 mg every 12 hours, hydromorphone 4 mg orally every two hours as needed for pain, nortriptyline, ondansetron, metoclopramide, calcium, vitamin D, and subcutaneous dalteparin. Her only documented allergy was to erlotinib, which previously caused a drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome as mentioned previously. She presented to an acute tertiary care center in the summer of 2011 with a pain crisis andsigns and symptoms of opioid toxicity, approximately three weeks after her last chemotherapy
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and radiation therapy and two weeks after the injection of denosumab. The baseline pain in her right ischium had increased over a period of days to include bilateral hips and lower back. She denied any saddle anesthesia, stool incontinence, or urinary retention. Her Palliative Performance Scale score had decreased from 60% to 40% in a matter of days. Signs of opioid toxicity included confusion and myoclonus. Significant findings on physical examination revealed an elevated blood pressure of 170/105, decreased power in the hips bilaterally, absent ankle reflexes, and normal rectal tone. The remainder of the physical examination was within normal limits. She was admitted to the palliative care inpatient service, and the opioid was rotated from oral hydromorphone to an intravenous (IV) infusion of fentanyl at a 50% dose reduction because of her opioid toxicity. Hydralazine was initiated to manage her elevated blood pressure. This patient’s previously expressed wishes included no attempts at cardiopulmonary resuscitation, and this was reconfirmed at the time of hospital admission. Her goals of care included investigation and management of any reversible causes of pain and confusion, plus optimizing symptom control. On the first day after admission, this patient developed a sudden increase in dyspnea and
Fig. 1. This electrocardiogram shows ST elevation in V2-V5 in our patient. Cardiac catheterization failed to find any coronary lesions.
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new onset anterior chest pain. She was found to be in acute congestive heart failure, with electrocardiogram (EKG) findings suspicious for an anterior ST-segment elevation myocardial infarction (Fig. 1). On discussion with the patient and her family, she clearly expressed the wish to have this acute event investigated and treated if possible. The cardiology service was consulted emergently. A bedside echocardiogram (Fig. 2) revealed signs of left ventricular apical ballooning without signs of overload or right ventricular failure, and there were no signs of pericardial effusion or tamponade. The left ventricular ejection fraction was 35%. An initial troponin I level was elevated at 3.2 mg/L (normal range 0e0.06). The patient underwent an urgent cardiac catheterization, which revealed normal coronary arteries with no signs of stenosis. Hence, a diagnosis of TC was made. The patient was transferred to the intensive care unit (ICU) for management with IV furosemide, IV nitrate infusion, oral metoprolol, oral spironolactone, and bilateral positive airway pressure. A decision was made to not monitor any cardiac enzymes as it would not affect the management of this patient. Over the ensuing days, the patient’s cardiac condition demonstrated clinical improvement with these supportive measures. Her oxygen requirements gradually decreased to the point where she required only low-flow oxygen by nasal prongs. She was successfully weaned off the IV nitrate and furosemide infusions. She was transferred from the ICU to the oncology floor under the palliative care service. Dyspnea
3
significantly improved throughout her hospitalization. A repeat echocardiogram at this time was not performed as the results would not have changed the current management. Unfortunately, the patient suffered additional complications in hospital unrelated to her TC, including an impending spinal cord compression from the metastatic disease to the thoracic spine, which necessitated a course of dexamethasone and five fractions of radiation therapy. After three weeks of hospitalization, the patient’s pain control was optimized on a continuous infusion of IV fentanyl administered by a continuous ambulatory delivery device (CADD) at a rate of 35 mg/hour, with a bolus dose of 45 mg every 30 minutes as needed for pain. Pain management was significantly improved and symptoms of opioid neurotoxicity had resolved. Her Palliative Performance Scale score on discharge was 30%. She was discharged home on an IV fentanyl infusion by continuous ambulatory delivery device ([CADD] as described previously), oral metoprolol, spironolactone, dexamethasone, metoclopramide, subcutaneous dalteparin, and home oxygen. Follow-up was to be provided by the home care nurses and a palliative care physician in her local community. The patient wished to receive endof-life care in her home surrounded by loved ones. Her prognosis was estimated to be within weeks to months of discharge. Although there was no further contact with our tertiary palliative care team after discharge, we were available for phone consultation with her local palliative care physician.
Comment
Fig. 2. This bedside echocardiogram shows a dilated akinetic ballooning of the apex along with a hyperdynamic base.
With the assistance of the Canadian Library of Family Medicine, a literature review of TC was undertaken. Ovid MEDLINEÒ MeSH search terms pertaining to TC and its synonyms (including transient apical ballooning syndrome, apical ballooning cardiomyopathy, stress-induced cardiomyopathy, GebrochenesHerz-Syndrom, stress cardiomyopathy, and broken heart syndrome) were used, with search dates from January 2007 to October 2011, yielding almost 70 articles describing the pathophysiology, etiology, diagnosis, and management of TC. Only English language
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articles were examined. A search of ‘‘cancer’’ or ‘‘neoplasms,’’ which automatically explodes all subtypes to include all cancer articles regardless of type, combined with TC and its synonyms, revealed four articles, concentrating on either chemotherapy- or radiation therapyinduced TC. A search for articles on ‘‘withdrawal,’’ combined with terms pertaining to TC, revealed eight articles. These articles discussed withdrawals from medications (including opioids) and alcohol as etiological factors leading to TC. Articles on pheochromocytoma catecholamine-induced pain were excluded as per the Mayo Clinic criteria for TC.2 No articles were found based on a search combining ‘‘pain crisis’’ or ‘‘pain crises’’ with TC and its synonyms, from the period of 1948 to October 2011. Oral consent to present this case report was obtained from the patient and her family, which was documented in the patient’s chart. Approval was obtained from the Queen’s University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board. TC, also known as stress-induced cardiomyopathy, transient apical ballooning, or ‘‘broken heart syndrome,’’ was first described in 1990 by Sato et al.2e4 The differential diagnosis includes acute coronary syndrome (ACS), angina pectoris, myocarditis, aortic dissection, cardiac tamponade, and Boerhaave syndrome.5 It is associated with a sudden nonischemic left ventricular dysfunction in which the left ventricle resembles a Japanese octopus trap (from which the condition gets its name), with a narrow neck and wide base.2 Patients may present with symptoms resembling an ACS, despite the absence of obstructive coronary artery disease on angiography. They can sometimes present with life-threatening and distressing flash pulmonary edema, cardiogenic shock, and ventricular arrhythmias.4,6 The prevalence of TC among patients with a suspected myocardial infarction is 0.7% e2.5%.4 Ninety-one percent of TC patients are women between the ages of 62 and 76 years.3,6 Treatment is typically supportive in nature, and TC usually resolves on average over 18 days (range 9e53 days).1 In-hospital mortality is estimated at 2%.4 Looking at all-cause mortality, the four year survival of patients with TC is no different than that in patients of an age- and sex-matched population.5
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However, the recurrence rate of TC within the four year period is 11.4%.6 Several theories exist regarding the etiology of this disorder, including coronary artery vasospasm and left ventricular outflow tract obstruction.4 The most accepted theory is that TC is catecholamine induced, from a combination of emotional and/or physical pain.4 In the literature, 44% of stressful events that initiate TC are emotional in nature, and 36% are physical.7 The criteria for diagnosing TC, as per the updated Mayo Clinic criteria,2 are as follows: 1. Transient abnormality of left ventricular contraction with akinesia of the apex and hyperkinesis of the base. Typically, the coronary arteries lack findings of stenosis, but the presence of stenosis does not exclude the possibility of TC. 2. Other combinations of akinesia and hyperkinesis are permitted, known as either ‘‘atypical’’ or ‘‘inverted’’ TC. 3. The motion abnormalities resolve in four to eight weeks, although in some patients, they can take up to one year to resolve. 4. The most common EKG changes are STsegment elevations in the chest leads V1eV6, with T-wave inversions beginning to form in all leads. 5. Pheochromocytoma, myocarditis, and physical stressors such as head trauma, seizures, and stroke should be excluded. The case presented definitely meets the updated Mayo Clinic criteria for TC. The patient developed sudden apical ballooning as seen on a bedside echocardiogram, with an ejection fraction of 35%. No baseline ejection fraction was known as the patient did not have any cardiac history or known risk factors for cardiac disease. EKG findings were suspicious for an ST-segment elevation myocardial infarction, but cardiac catheterization failed to find any coronary lesions. From a cardiac standpoint, the patient improved clinically with supportive management. Initial treatment was in the ICU with bilateral positive airway pressure, IV furosemide, and nitrates. On discharge from hospital, the patient continued on oral metoprolol and spironolactone for her TC. Cardiology recommended that she could return in six months time for a repeat echocardiogram. The plan at that time would be to discontinue metoprolol and spironolactone if her motion
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TC and Cancer-Related Pain Crisis
abnormalities had completely resolved on reassessment. However, the patient declined to return to hospital as it was her wish to remain at home until death. Although we did not specifically rule out the possibility of pheochromocytoma (such as through measurements of urinary and plasma fractionated metanephrines and catecholamines), the fact that the patient lacked any previous episodes of hypertension, combined with a lack of headache, diaphoresis, or tachycardia, made such a diagnosis less likely. As a palliative care physician, it is important to remember that TC mimics an ACS and initially one cannot differentiate the two. The decision of whether to further investigate a suspected ACS depends greatly on the patient’s goals of care. Factors to bring into a discussion about goals of care could include the state of the patient’s disease, the patient’s functional status and rate of decline, and current and projected quality of life. In the case of our patient, she had a rapid decrease in functional status over a period of days and wished to have investigations and treatment for potential reversible conditions. She wished to maximize her chance of being discharged to be able to die at home surrounded by her family. She understood that this acute cardiac event had the potential of ending her life sooner than her underlying disease and, therefore, wanted us to attempt to reverse it. Only after this discussion had taken place, did we proceed with further investigation and treatment. Generally, the treatment of TC, once diagnosed, is supportive and empirical in nature.6 Cardiology and internal medicine specialists should be involved from the outset. The literature supports management of TC with beta blockers, given the likely mechanism of catecholamine-induced myocardial stunning, but there is no available evidence of benefit in preventing recurrence of TC.6 Hemodynamically stable patients also may benefit from an angiotensin-converting enzyme inhibitor, although again there is no clear evidence for long-term benefit in prevention of recurrence.6 The literature advises the administration of anxiolytic agents, especially if a physical or emotional stressor is expected to continue long term.6 For the treatment of congestive heart failure, diuretics have been shown to be effective.6 The treatment of
5
hemodynamically unstable patients is beyond the scope of this case report, and specialist consultation would be highly recommended. Although experimental data suggest that estrogen therapy may have a role in the prevention of TC in postmenopausal women, no randomized controlled studies have been performed, and thus, no recommendations can be made.6 As mentioned in the literature search, no prior case reports describing cancer-related pain crisis as a contributory precipitating etiology for the development of TC could be found. Two case reports have described the development of TC after administration of 5-fluorouracil (5-FU) chemotherapy. The first case occurred two weeks after administration of 5-FU,8 and the second case occurred 24 hours after administration.9 Two cases also have been reported after combrestatin-based chemotherapy used in the treatment of anaplastic thyroid cancer, one occurring 18 hours after administration and the second occurring immediately after chemotherapy administration.10 Our patient never received 5-FU or combrestatin-based chemotherapy regimens. However, it is possible that the administration of a chemotherapy agent and monoclonal antibody, three and two weeks, respectively, before presentation, may have contributed to the development of TC in our patient. One case report has described radiation therapy-induced TC, 12 days after administration, although the radiation in that case report was directed at the patient’s chest,11 which could have contributed to an increased risk of developing TC if the heart was in the radiation field. This differs from our patient, who received radiation therapy to the hip three weeks before presentation. TC also has been reported after alcohol withdrawal,12 metoprolol withdrawal,13 poisoning with cardiotoxic drugs,14 and postoperatively.15 The unifying theory among these case reports is that TC is catecholamine induced. This case report lends further credence to that theory as cancer-induced pain crisis is a state of high circulating catecholamines. One possible contributing factor to our patient developing TC was the opioid rotation with dose reduction because of opioid toxicity. At the time of opioid rotation, her pain was not well controlled. In one case of opioid withdrawal,16 a patient developed TC after being
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unable to obtain prescription opioids for one week. The baseline dose of opioid was not clearly stated in the article. This case in the literature is different from our case, in that it describes a patient who developed a seizure and required intubation. Another case described in the literature was one of methadone withdrawal,17 in which a patient on 120 mg/day of methadone was reportedly given naltrexone to stop alcohol consumption and developed an acute opioid withdrawal syndrome. Our patient was not given an opioid antagonist, but, because of opioid toxicity, was rotated to a different opioid with a dose reduction, as per clinical practice guidelines.
2. Sinning Ch, Keller T, Abegunewardene N, et al. Tako-Tsubo syndrome: dying of a broken heart? Clin Res Cardiol 2010;99:771e780.
Conclusion
7. Pernicova I, Garg S, Bourantas CV, Alamgir F, Hoye A. Takotsubo cardiomyopathy: a review of the literature. Angiology 2010;61:166e173.
Pain crises are often seen in patients with cancer, but potential cardiac complications of these crises are rarely considered or discussed. TC is a diagnosis that should be considered in patients presenting with signs and symptoms mimicking a myocardial infarction, especially after a period of physical and/or emotional stress. Early recognition and management of this condition can help prevent morbidity and mortality and can contribute to improvement in patients’ quality of life. Based on the literature search we conducted, to our knowledge, this case report is the first to attribute a cancer-related pain crisis as a contributory precipitating event for the development of TC. This report also lends further evidence to the leading theory that TC is catecholamine induced in nature.
Disclosures and Acknowledgments The authors thank the The Canadian Library of Family Medicine for assistance with the literature search, Dr. A. Johri from Queen’s University for assistance with interpretation of the echocardiogram, and the Queen’s University Palliative Care Medicine Program. Dr. S. Singh also thanks Dr. J. Tang for her ongoing support. This work received no funding, and the authors have no conflicts of interest to declare.
References 1. Bielecka-Dabrowa A, Mikhailidis DP, Hannam S, et al. Takotsubo cardiomyopathydthe current state of knowledge. Int J Cardiol 2010;142:120e125.
3. Tarkin JM, Khetyar M, Kaski JC. Management of Tako-tsubo syndrome. Cardiovasc Drugs Ther 2008; 22:71e77. 4. Nef HM, M€ ollmann H, Akashi YJ, Hamm CW. Mechanisms of stress (Takotsubo) cardiomyopathy. Nat Rev Cardiol 2010;7:187e193. 5. Tomich EB, Luerssen E, Kang CS. Takotsubo cardiomyopathy [Internet]. New York: Medscape, 2012. Available from http://emedicine.medscape. com/article/1513631-differential. Accessed April 9, 2012. 6. Palecek T, Kuchynka P, Linhart A. Treatment of Takotsubo cardiomyopathy. Curr Pharm Des 2010; 16:2905e2909.
8. Gianni M, Dentali F, Lonn E. 5 fluorouracilinduced apical ballooning syndrome: a case report. Blood Coagul Fibrinolysis 2009;20:306e308. 9. Basselin C, Fontanges T, Descotes J, et al. 5-Fluorouracil-induced Tako-Tsubo-like syndrome. Pharmacotherapy 2011;31:226. 10. Bhakta S, Flick SM, Cooney MM, et al. Myocardial stunning following combined modality combretastatin-based chemotherapy: two case reports and review of the literature. Clin Cardiol 2009;32:E80eE84. 11. Modi S, Baig W. Radiotherapy-induced Takotsubo cardiomyopathy. Clin Oncol (R Coll Radiol) 2009;21:361e362. 12. Alexandre J, Benouda L, Champ-Rigot L, Labombarda F. Takotsubo cardiomyopathy triggered by alcohol withdrawal. Drug Alcohol Rev 2011;30:434e437. 13. Jefic D, Koul D, Boguszewski A, Martini W. Transient left ventricular apical ballooning syndrome caused by abrupt metoprolol withdrawal. Int J Cardiol 2008;131:e35ee37. 14. Hantson P, Beauloye C. Myocardial metabolism in toxin-induced heart failure and therapeutic implications. Clin Toxicol (Phila) 2012;50:166e171. 15. Daly MJ, Dixon LJ. Takotsubo cardiomyopathy in two preoperative patients with pain. Anesth Analg 2010;110:708e711. 16. Yousuf MA, Adjei S, Kinder B. A 58-year-old woman with ST-segment elevation, seizures, and altered mental status in the setting of opiate withdrawal. Chest 2009;135:1098e1101. 17. Lemesle F, Lemesle F, Nicola W, Pierre JonvilleB era A. First case of stress cardiomyopathy as a result of methadone withdrawal secondary to drug-drug interaction. Am J Emerg Med 2010;28:387.
