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by Andrew Thurston

Case:
Ms. S.T. is a 26-year-old woman with metastatic colorectal carcinoma who is admitted to the hospital with worsening abdominal pain. Imaging of the abdomen and pelvis demonstrates further progression of her cancer despite second line palliative chemotherapy. In addition to abdominal pain, she reports decreased appetite and nausea. No family is at bedside.

Despite aggressive titration of IV dilaudid via a PCA, she continues to report excruciating pain and frequently asks the nurses for higher doses of opioids. On evaluation, she spends the first few minutes describing her pain in great detail, but the subject quickly changes to other forms of distress. She spends a lot of time talking about her fear of dying, about how her cancer has taken over her life. She describes her dream to be the first person in her family to graduate from college, and her hopes to provide a better life for her family. She speaks passionately of her desire to help others, and her distress at not being able to help herself. She is angry at her cancer, at her doctors for not catching it sooner, and at God for “abandoning” her. Her parents are deeply religious and tell her that “things are in God’s hands,” but hearing this only makes her more upset. When discussing her concerns and general distress, her pain seems to fade into the background, and she only pushes her PCA once in the hour visit.

A multi-modal and interdisciplinary approach is put in place to help address her existential distress and total pain. The chaplain visits regularly, family and friends are encouraged to visit; psychiatry is involved to address concerns of depression. She wonders if there is a way to help give back, and take her mind off of things while in the hospital.

Discussion:
Existential distress is quite common at the end of life, with some studies suggesting that 50-80 percent of terminally ill patients experience troubling thoughts about death, and only a minority achieve acceptance. While general consensus supports a multi-disciplinary approach to addressing existential distress, some more specific strategies exist such as cognitive existential group therapy, dignity psychotherapy, and meaning-centered group psychotherapy.

Another strategy is the use of narrative medicine through reflective writing. In fact, some studies have even shown benefits of emotional disclosure through patient narrative on pain and well-being scales, showing that narratives with higher emotional disclosure resulted in a significant decrease in pain and an increase in well-being scores.

Recognizing that a person’s illness is part of his life story acknowledges that we are all part of a larger life narrative – the story of ourselves, of our relationships, our love and suffering. We tell stories on a daily basis, whether consciously or subconsciously.

But in the setting of illness, personal narratives and identities often crumble. Rita Charon and others argue that narrative medicine is a model for empathy, and is beneficial not only to our patients, but to ourselves as well. Palliative care experts use narrative medicine often on a daily basis – giving patients and family members time to explore their illness through storytelling, and eliciting their goals and values in the process.

A specific technique in narrative medicine is the generation of a reflective piece through the 55-word story. The premise is simple: write for ten minutes about any topic or concern, and then spend another 10 minutes narrowing down the narrative to 55 words, cutting out the unnecessary words. This is a quick, and often very powerful, reflective tool. For patients searching for a legacy project, the exercise of writing – whether through an exercise like the 55-word story, or through journaling or some other form of expression – can serve this purpose as well.

Resolution of Case:
Ms. S.T. decided that journaling would be a way to express her frustrations, but at the same time share her life lessons with her siblings and other young adults living with cancer. In this regard, she felt like it would be a good legacy project and a way to further give back at the end of her life. She often spent hours a day writing in her journal, and found that this helped ease her mind and took her thoughts away from her pain. She made it her goal to publish her journal so that it could continue helping others long after she had died.

References:

1. Bolmsjo, I. Existential issues in palliative care – interviews with cancer patients. Journal of Palliative Care 2000;16(2):20-24.
2. LeMay, K., Wilson, K.G. Treatment of existential distress in life threatening illness: A review of manualized interventions. Clinical Psychology Review 2008;28:472-493.
3. Cepeda, M. Soledad et al. Emotional Disclosure Through Patient Narrative May Improve Pain and Well-Being: Results of a Randomized Controlled Trial in Patients with Cancer Pain. J Pain Symptom Manage 2008;35(6):623-631.
4. Moore, R.J., Hallenbeck, J. Narrative Empathy and How Dealing with Stories Helps: Creating a Space for Empathy in Culturally Diverse Care Settings. J Pain Symptom Manage 2010;40(5):471- 476.
5. Lindemann, N.H. Damaged Identities – Narrative Repair. Ithaca, NY: Cornell University Press, 2001. 
6. Charon, R. Narrative Medicine. JAMA 2001;286(15):1897-1902. (OPEN ACCESS PDF with log in)
7. Marchand, L., Fleming, E., Mastrocola, J., Gasper, A., Marty, E. Noticing…Reflecting…Healing: 55-Word Stories. AAHPM Quarterly 2014;15(1):7.

Photo Credit: "Narrative Medicine" by unknown

Pallimed Case Conference Disclaimer: This post is not intended to substitute good individualized clinical judgement or replace a physician-patient relationship. The case and discussion is published as a means to illustrate important teaching points in healthcare. Patient details may have been changed by Pallimed editors to ensnure anonymity. Links and minor edits are made for clarity and Pallimed editorial standards

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by Jordan Keen

Case:
SM is a 25-year-old female with progressively worsening rhabdomyosarcoma despite multiple rounds of chemotherapy and surgery. She presented to the emergency department with worsening of her chronic tumor-related abdominal pain and new, diffuse pain of the muscles and joints. Family reported she had been experiencing episodes of confusion and hallucinations over the past week. Her home pain regimen of long-acting morphine and as needed oxycodone had been titrated aggressively over the past month in an attempt to control her pain (600mg total daily oral morphine equivalents).

When first evaluated by the palliative care consult service, she was in severe distress. She described severe, 10/10, diffuse pain. On exam there was generalized tenderness of the abdomen, as well as her shoulders, upper legs, and lower back. She was exhibiting myoclonic jerks of her upper extremities every 3-4 seconds. Although she was alert and oriented, she was easily distracted during the exam and required frequent redirection.

Our palliative care team was concerned about opioid-induced hyperalgesia (OIH). Suspicion was high given the paradoxical worsening of her pain despite high doses of opioids and the neuroexcitatory signs and symptoms (myoclonus, confusion, and hallucinations) she was exhibiting. Therefore, it was decided to lower the overall dosage and switch her opioid regimen in an attempt to reverse OIH. Her long-acting morphine was discontinued and replaced with methadone 5mg three times per day. Her as-needed oxycodone dose was reduced from 30mg to 5mg every 4 hours. To control the myoclonus, low dose lorazepam was administered three times per day.

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Discussion:
Opioid-induced hyperalgesia (OIH) is a rare syndrome of increasing pain, often accompanied by neuroexcitatory effects, in the setting of increasing opioid therapy. Clinicians should consider OIH in patients on high dose opioids or during a period of rapid opioid escalation. While case reports show a wide range of dosages can provoke this syndrome, the majority of patients are on very high doses, often greater than 1000mg oral morphine equivalents per day and typically via parenteral routes (IV and intrathecal). Morphine is by far the most common opiate implicated in OIH. Hydromorphone and oxycodone, members of the same class of opiate as morphine (phenanthrenes), can also cause OIH, but oxymorphone has not yet been reported to cause it. Methadone, a synthetic opioid in the class of diphenylheptanes, and fentanyl, a synthetic opioid in the class of phenylpiperidine, are considered less likely to precipitate OIH.

Existing data suggests that OIH is caused by multiple opioid-induced changes to the central nervous system including:

• Activation of N-methyl-D-aspartate (NMDA) receptors
• Inhibition of the glutamate transporter system
• Increased levels of the pro-nociceptive peptides within the dorsal root ganglia
• Activation of descending pain facilitation from the rostral ventromedial medulla
• Neuroexcitatory effects provoked by metabolites of morphine and hydromorphone

OIH can be confused with tolerance as in both cases patients report increased pain on opioids. The two conditions can be differentiated based on the patient’s response to opioids. In tolerance, the patient’s pain will improve with dose escalation. In OIH, pain will worsen with opioid administration. This paradoxical effect is one of the hallmarks of the syndrome. On physical exam, patients are grimacing in pain with moderate-to-severe distress, myoclonus, altered mental status or delirium and often allodynia (pain due to non-painful stimuli, such as light touch).

Typically, if you suspect OIH, you should get a pain or palliative care consultation because it will seem wrong to decrease opiates in a patient in severe pain. Opiate dose reduction and rotation to a synthetic opioid such as fentanyl or methadone is recommended. Methadone has the additional benefit of NMDA antagonism. It is not surprising that methadone has been shown to improve or resolve OIH given the role NMDA activation plays in causing OIH. Adjuvant therapies, such as acetaminophen or neuropathic pain medications, should be considered as they may decrease the need for opioids. Benzodiazepines may be a temporary addition to manage myoclonus as the OIH resolves.

Symptoms of OIH do resolve when patients are treated with the above strategies. However, it can be long and difficult to wean some patients to a low enough level of opioids to stop OIH. Existing literature does not address any long-term consequences of OIH. We hope to see more research on this subject.

Over the next 48 hours in the hospital, her myoclonus improved. Her pain and mental status improved more slowly. It took a week to re-establish control of her pain. At the time of discharge, she rated her pain as 3/10. Her new pain regimen consisted of methadone 10mg three times a day and oxycodone 5mg every 4 hours as needed.

References:
1. Chu, L. Opioid-induced Hyperalgesia in Humans: Molecular Mechanisms and Clinical Considerations. The Clinical Journal of Pain Issue: Volume 24(6), pp 479-496. 2008.

2. Smith, M. Neuroexcitatory Effects Of Morphine And Hydromorphone: Evidence Implicating The 3-GlucuronideMetabolites. Clinical and Experimental Pharmacology and Physiology, 27, pp 524–528. doi: 10.1046/j.1440-1681.2000.03290. 2000.

3. Mao, J. Opioid-induced abnormal pain sensitivity. Current Pain and Headache Reports. Volume 10, Issue 1, pp 67-70. 2006

4. Lee, M et al. A Comprehensive Review of Opioid-Induced Hyperalgesia. Pain Physician 2011; 14:145-161. ISSN 1533- 3159. Open Access PDF

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by Shannon Haliko

Case:
Mr. K is a 58-year-old male with diabetes and ischemic cardiomyopathy which contributed to end-stage heart failure necessitating circulatory support with a left ventricular assist device (LVAD) implanted one year ago. His post-operative course has been complicated with multiple admissions for infection resulting in several operative revisions and kidney injury. He was admitted with a similar presentation prompting a moment of reflection by his primary team.

Over the last year, Mr. K had declining involvement in his own care, which included poor attention to his medications and wound dressings. It was clear that Mr. K’s lack of involvement was contributing to his frequent admissions, but the root of Mr. K’s suspected apathy was unclear. The Palliative Care team was consulted to assess the patient’s goals of care.

Interviewing Mr. K was challenging. Though he was pleasant and cooperative, he was distractible. Attempts to elicit his values would take the listener on a long, circumferential and circumstantial path without a clear ending. Despite his confusing stories, he clearly explained a hope to regain his ability to perform tasks on his farm. He also succinctly described the importance of sharing his life with family, including several new grandchildren. While this information helped clarify his values and healthcare goals, the team questioned his cognitive ability. Because we were unable to distinguish between depression, apathy, and cognitive impairment, we asked for a formal psychiatry consult.

Mr. K described his mood as “down in the dumps” for the last two years; he felt his heart failure symptoms prevented him from performing even simple activities on his farm. Unfortunately, he had not noticed any improvement in his energy with LVAD implantation one year ago, but did reflect that he sustained damage to his liver and kidney. Despite prominent feelings related to his illnesses and poor functional status, he remained hopeful that he would recover. Though he provided an accurate general picture of his health state, he gave inconsistent or superficial answers to detailed inquiry about recent complications. He denied feelings of anxiety, hopelessness, guilt or suicidal thoughts and had not noticed any changes in appetite or sleep, or hallucinations. He still found interest in television shows and NASCAR racing.

On exam, he was disheveled and often violated social norms of the interview (interrupting his own storytelling to make an unrelated phone call, commenting on the TV programs currently showing). He had no abnormalities in muscle bulk, tone or movement. There was no dysmetria, tremor or gait disturbance but his Luria test (for executive motor control) was abnormal. His speech was broken into single sentence or phrase fragments with a rare moment of word searching with use of circumlocutions.

His affect was reactive, full and incongruent with his stated mood of depression. His thought content, while future oriented, was indeed impaired as noted by the Palliative Care team, with a particular focus on concrete thought processes. Memory of his own medical history was inconsistent, and his delayed recall of three objects was impaired. His inconsistencies also manifested when discussing insight for his own illness, with a tendency to over-simplify his condition or health consequences.


Discussion:
Mr. K’s exam is consistent with a mild neurocognitive disorder (NCD) with mixed features (concentration, executive function, and mild memory and language impairments). NCD is a new diagnosis found in the update of the DSM-V. This update of psychiatric diagnosis guidelines re-organizes the previous diagnoses of mild cognitive impairment (MCI) and dementia to a neurocognitive disorder (NCD) of either mild or major impairments. NCD is defined as “a change from previous level of function with noted impairment in one of the following domains: complex attention; learning or memory; language; perceptual-motor; social cognition and executive function”¹. The distinction between mild or major impairment is determined by the ability to live independently. Subtypes of NCD can be described by the dementia’s presumed etiology, for example Alzheimer’s type. The definition of NCD yields high inter-rater reliability among clinicians, but the diagnosis is too new to be sure of its prevalence. MCI, the closest approximation of mild NCD, has a prevalence of between 3-42% reported across studies of at-risk inpatients and outpatients.² The prognosis related to NCD is uncertain. Some patients with mild NCD progress to major NCD, but with others the disease is stable or may revert to normal cognition.

There are many hypotheses for the pathophysiology behind neuro-degeneration seen in NCD, including vascular deficits and inflammatory pathways, but no unifying theory has been confirmed. Effective pharmacologic treatment of NCD is currently lacking. Anticholinesterase inhibitors should be utilized only in mild to moderate Alzheimer’s dementia³, but recent guidelines to support this practice are either weak⁴ or discouraging⁵. Promising agents currently include noradrenergic and polyphenolic compounds (ginkgo biloba, wine and some vegetables). Non-pharmacologic therapies (exercise, diet, cognitive stimulation) show variable effects, have poor generalizability, or impermanent results. Other non-pharmacological treatments (cognitive behavioral therapy) have focused on neuropsychiatric symptoms (mood disturbance, apathy, agitation and psychosis) and show improvement in symptoms but not underlying cognitive impairments.⁶ Pharmacologic treatment of the same symptoms has not been found beneficial and may be associated with a more rapid decline⁷.
Mr. K has several risk factors for NCD (heart failure with its metabolic and perfusion derangements, atherosclerosis, bypass surgery and the LVAD itself)⁸. Up to 60% of patients demonstrate some level of cognitive deficit both before and after implantation.⁹ Additionally, depression is present in 20-30% of LVAD patients^10,11, and is often missed, misdiagnosed12 or even confused with cognitive impairment.

Given that depression and NCD often co-occur, it is important to routinely screen patients for both. The PHQ-2, a rapid two question screen for depression that has a sensitively of 97% and specificity of 96%.13 An optimal screening test for NCD remains to be determined, but the mini-Kingston standardized cognitive assessment-revised (mini-KSCAr) yields the highest sensitivity and specificity studied to date. (Detection of mild NCD: sensitivity 81% and specificity 85%; Detection of major NCD: sensitivity 100% specificity 91%. Comparators include Mini-Mental State Examination (MMSE)*, the clock drawing test (CDT), and Montreal Cognitive Assessment (MoCA))14. Identification of complex or concurrent disorders would likely benefit from referral to a specialist for standardized neurocognitive testing and treatment.

*MMSE is copyrighted - see GeriPal for more - Ed.

Case Resolution:
At examination, Mr. K agreed to pursue rehabilitation on discharge in a care facility rather than his home. He clearly described the risk, benefits and alternatives to the choice supporting our assessment of capacity for this decision. However, we expect Mr. K’s capacity will be limited for more complex decisions, and the primary team was alerted that appropriate evaluation of his capacity should be undertaken for each future healthcare decision.

References:
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5).; 2013. doi:10.1176/appi.books.9780890425596.744053.

2. Panza F, D’Introno A, Colacicco AM, et al. Current epidemiology of mild cognitive impairment and other predementia syndromes. Am J Geriatr Psychiatry. 2005;13(8):633-644. doi:10.1176/appi.ajgp.13.8.633.

3. Dementia | 1-recommendations | Guidance and guidelines | NICE. http://www.nice.org.uk/guidance/cg42/chapter/1-recommendations#interventions-for-cognitive-symptoms-and-maintenance-of-function-for-people-with-dementia. Accessed June 3, 2015.

4. Doody RS, Stevens JC, Beck C, et al. Practice parameter: Management of dementia (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001;56(9):1154-1166. doi:10.1212/WNL.56.9.1154.

5. Daviglus ML, Bell CC, Berrettini W, et al. NIH state-of-the-science conference statement: Preventing Alzheimer’s disease and cognitive decline. NIH Consens State Sci Statements. 2010;27(4):1-30. Accessed June 1, 2015.

6. Sachs-Ericsson N, Blazer DG. The new DSM-5 diagnosis of mild neurocognitive disorder and its relation to research in mild cognitive impairment. Aging Ment Health. 2015;19(1):2-12. doi:10.1080/13607863.2014.920303.

7. Rosenberg PB, Mielke MM, Han D, et al. The association of psychotropic medication use with the cognitive, functional, and neuropsychiatric trajectory of Alzheimer’s disease. Int J Geriatr Psychiatry. 2012;27(12):1248-1257. doi:10.1002/gps.3769.

8. Cannon JA, McMurray JJ, Quinn TJ. “Hearts and minds”: association, causation and implication of cognitive impairment in heart failure. Alzheimers Res Ther. 2015;7(1):22. doi:10.1186/s13195-015-0106-5.

9. Petrucci RJ, Truesdell KC, Carter A, et al. Cognitive dysfunction in advanced heart failure and prospective cardiac assist device patients. Ann Thorac Surg. 2006;81(5):1738-1744. doi:10.1016/j.athoracsur.2005.12.010.

10. Baba A, Hirata G, Yokoyama F, et al. Psychiatric problems of heart transplant candidates with left ventricular assist devices. J Artif Organs. 2006;9(4):203-208. doi:10.1007/s10047-006-0353-0.

11. Rutledge T, Reis VA, Linke SE, Greenberg BH, Mills PJ. Depression in heart failure a meta-analytic review of prevalence, intervention effects, and associations with clinical outcomes. J Am Coll Cardiol. 2006;48(8):1527-1537. doi:10.1016/j.jacc.2006.06.055.

12. Boland RJ, Diaz S, Lamdan RM, Ramchandani D, McCartney JR. Overdiagnosis of depression in the general hospital. Gen Hosp Psychiatry. 1996;18(1):28-35. doi:10.1016/0163-8343(95)00089-5.

13. Maurer DM. Screening for depression. Am Fam Physician. 2012;85(2):139-144. http://www.ncbi.nlm.nih.gov/pubmed/22335214. Accessed April 22, 2015.

14. Liew TM, Feng L, Gao Q, Ng TP, Yap P. Diagnostic utility of Montreal Cognitive Assessment in the Fifth Edition of Diagnostic and Statistical Manual of Mental Disorders: major and mild neurocognitive disorders. J Am Med Dir Assoc. 2015;16(2):144-148. doi:10.1016/j.jamda.2014.07.021.

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by Yael Schenker, MD, MAS

Case:
A 58-year old man receives a left ventricular assist device (LVAD) for chronic end-stage heart failure in 2010. His LVAD is initially placed as a bridge to transplant. However his post-operative course is complicated by persistent chronic infection, multiple embolic strokes and prolonged hospitalization. He is taken off the transplant list. In 2012 he is readmitted to the hospital from a long-term acute care facility for aortic valvuloplasty and LVAD weaning studies. This hospitalization is complicated by a hematoma causing nerve compression in his right leg and he is no longer able to walk. He tells the cardiothoracic surgery team that he wants his LVAD to be turned off and the team calls a palliative care consult.

Discussion:
The left ventricular assist device (LVAD) was initially designed as a bridge to heart transplant. Open-heart surgery is required to implant an LVAD, which is attached to the left ventricle and the aorta in parallel with the patient’s native cardiovascular system. A small pump is placed in the patient’s abdominal cavity and connected to external battery controlled system that can be worn over or under clothing. (1)

In 2003, the LVAD was approved as destination therapy (LVAD-DT) for patients with chronic end-stage heart failure who are not candidates for a heart transplant. This decision arose from a prospective randomized controlled trial conducted between 1998 and 2001 comparing LVAD-DT to optimal medical management (OMM) for chronic endstage heart failure, in which patients receiving LVADDT showed improved survival over patient receiving OMM at 1-year (52% vs. 25%, p = 0.002) and 2-years (23% vs. 8%, p = 0.09). (2) Improved survival rates with LVADs are coupled with frequent and disabling complications including serious infections and strokes. (1)

Increasing numbers of patients living longer with LVADs has led to growing recognition of an important role for palliative care that may begin before implantation of an LVAD and continue through the end of life. (3) A palliative care clinician may be asked to assess whether LVAD implantation is consistent with a patient’s goals and/or to assist with a transition to comfort-oriented treatment if the decision is made not to implant a device. Palliative care clinicians may help patients and families to complete advance directives that name a surrogate decision maker and describe the circumstances under which withdrawal of the LVAD device would be desired. Palliative care clinicians may also help to assess physical, psychological and spiritual needs that arise with LVAD use and refer patients and families to appropriate resources. Transitions in care, such as the determination that a patient with an LVAD is no longer a candidate for heart transplant, are important opportunities for palliative care clinicians to acknowledge emotions and provide support. A recent article by Goldstein et al provides sample communication techniques for each of these time points. (3)

Most commonly, palliative care clinicians are called to assist with the decision about whether to discontinue a LVAD, as occurred in this case of the month. At this advanced disease stage, not all patients will be able to communicate or have capacity to make decisions. However, conversations should include patients if they are able to participate and want to be involved. A first step is to assess what the patient and/or family understand about heart failure and the LVAD. Opening with a simple question such as “tell me what you understand about your disease” or “tell me what the doctors have talked with you about so far” can offer significant insights.

Clinicians should follow up by asking what the patient and/or family want to know before offering additional information or clarifying misperceptions. The next step is to talk about overall goals of care. “Help me to understand what is important to you” is a good question to initiate this discussion. In this case, the patient described an acceptable quality of life as being able to walk and live independently. Once the patient’s goals have been articulated, the physician can help to develop a treatment plan that matches the patient’s values. (3) In this case, after multiple discussions, the patient made it clear that the burdens of the LVAD now outweighed its benefits for this patient.

Ethical guidelines and legal precedents support a patient’s right to request the withdrawal of any medical intervention, regardless of whether the patient is terminally ill and regardless of whether the intervention prolongs life. (4) If a patient lacks capacity, these rights extend to the appropriate surrogate decision maker. No ethical or legal distinction is made between different types of life-prolonging interventions (i.e., LVADs vs. feeding tubes vs. hemodialysis). Some clinicians have moral objections to turning off an LVAD. In such cases, the clinician should inform the patient of these objections without imposing his or her personal beliefs and help to find a colleague who can fulfill this role.

Turning off an LVAD requires a coordinated effort between physicians and nurses. The palliative care team can be helpful in answering questions and providing support for clinical staff as well as the patient and family. Most often when a LVAD is turned off the patient dies within minutes. However, if there is intrinsic heart function the patient may live for several days. Patients and families should be prepared for these outcomes. Medications such as opioids and benzodiazepines are used to ensure that the patient is comfortable. Premedication is important because most patients will have a significant decrease in cardiac output after the device is turned off.

Resolution:
The LVAD was turned off at the patient’s bedside. Morphine was given by both bolus and infusion to help control symptoms of dyspnea after the LVAD was turned off. He died comfortably approximately 48 hours later.

References:
1. Rizzieri AG, Verheijde JL, Rady MY, McGregor JL. Ethical challenges with the leftventricular assist device as a destinationtherapy. Philos Ethics Humanit Med. 2008;3:20. (OPEN ACCESS PDF)

2. Rose EA, Gelijns AC, Moskowitz AJ, Heitjan DF, Stevenson LW, Dembitsky W, et al. Long term use of a left ventricular assist device forend-stage heart failure. N Engl J Med. 2001;345(20):1435-43. (OPEN ACCESS PDF)

3. Goldstein NE, May CW, Meier DE. Comprehensive care for mechanical circulatorysupport: a new frontier for synergy withpalliative care. Circ Heart Fail. 2011;4(4):519- 27. (OPEN ACCESS PDF)

4. Lampert R, Hayes DL, Annas GJ, Farley MA, Goldstein NE, Hamilton RM, et al. HRS ExpertConsensus Statement on the Management ofCardiovascular Implantable Electronic Devices(CIEDs) in patients nearing end of life orrequesting withdrawal of therapy. Heart Rhythm. 2010;7(7):1008-26.


Pallimed Case Conference Disclaimer: This post is not intended to substitute good individualized clinical judgement or replace a physician-patient relationship. It is published as a means to illustrate important teaching points in healthcare. Patient details may have been changed by Pallimed editors to help with anonymity. Links and minor edits are made for clarity and Pallimed editorial standards.

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by Robert Arnold, MD

Case:

Doctors find it hard to talk about prognosis for a variety of reasons. Sometimes we do not like to talk about it because we are afraid that if we talk about it, it will happen –a self-fulfilling prophecy. I think this is often a reason that some doctors do not like to make patients DNR - they worry that if we make the patient DNR that we will not try as hard to correct problems and thus they be more likely to have a cardiac arrest (the data is controversial and this may be true). Other times, we do not like to talk about it because it means predicting the future, and when you predict the future you are often wrong (what I call “the weatherman phenomenon”). Patients or families may get mad when our predictions are incorrect which may lead to difficult conversations in which we feel bad. Doctors, not wanting to be wrong or feel inadequate, find it easier to be vague (“He is very sick and may not do well” is similar to the weatherman saying, “It is going to get brighter as the day goes along before darkness sets in”).

Discussion:

The problem is that prognostic information, like the weatherman's predictions, is vital to people's lives. It is hard to make decisions about medical interventions, about when families should come to visit their sick loved one, about when to have serious conversations without some idea of what the future might bring. For that reason, patients and families are often frustrated when doctors refuse to make any predictions about what might happen in the future. Families understand that the future is unpredictable, and the doctors are not all knowing and cannot know the future. Yet, they still want to have some ideas about what we are thinking because like weathermen, while we are not always right or wrong, we do have some expertise in prognostication.

For that reason, I have assembled four general hints to improve your ability to help the family think about prognostic information. (These recommendations assume that the patient/family wants to know prognostic data – about 75% do according to studies.) The purpose of these rules of thumb is to help the family begin to think about what their loved one would say about these possible futures.

Now for the four things that you might want to do:

1) Place your information in context. It is ok to admit our limitations in prognostication (“I do not have a crystal ball”). Doing this places your prognostication in context and is honest. However, it needs to be followed by an offer to provide information based our expertise and the available data (“I can however give you our best prediction, based on our experience and expertise, about what we think the future will look like”)

2) Offer outcomes as best, worst and most-likely. Toby Campbell at the University of Wisconsin has talked about the helpfulness of talking to patients and/or families about the best, the worst and the most likely outcomes. What I like about this formulation is that I do not have to be right. I can be hopeful about what may happen if everything goes well and yet it also allows me to be realistic about the most likely outcomes. It also allows space to be pessimistic about what the alternatives are.

This formulation is helpful to families because it gives them a range of outcomes to get their head around. They can think about what it would mean if the “best” outcome is one which the patient would find undesirable. If the most likely outcome is the patient is going to be in a nursing home, they have an incentive to start talking to the social worker about disposition. Finally, talking about “worst” outcomes is a chance to think about what outcomes would be “worse than death” for their loved one.

3) Include short and long term prognoses. Remember when we prognosticate to think not only about this hospitalization but also about the next 30 days, 90 days and year. It is often the case, particularly when patients are in the hospital, that we prognosticate for the duration of the stay that we are responsible for and forget to talk about the bigger picture. For patients and families the question often is not only what are we going to think is going to happen in the short term, but also to give a sense of what we think the longer term will be like. (Please see e-prognosis.com for what I think is the best website on this data.)

4) Include functional prediction in addition to mortality predictions. Finally, when you talk about prognosis, remember to talk both about mortality and about function. Most people in America are not vitalists – that is surviving with no cognitive, physical or social function – is often not a good outcome. Given that they are not vitalists, it is important to get again your sense of what three months from now the best, worst and most likely outcomes are so that they can begin to think about what their loved one might think about those possible realities. Talk both about functional status expectations and what that means for setting of care (home independently, home with 24hr care, SNF)

Resolution of the case:

You do not have to be quantitative in your description of what you think the future is going to be – in fact, the data suggests that patients' and families' understanding is just as good when we use qualitative terms as when we try to give percentages.

It is also important to remember that when you give this information it is often heard as disturbing news to the patient or family because by you naming it, you make it more real even if they were not worrying or thinking about it. Strong emotions are likely to follow your predictions, and it will take some time to acknowledge these and ask what questions they have about your thoughts of the future.

Someone said that 90% of life is just showing up. This saying might be true of prognostication – you have to show up and give your most informed views (you do not have to be right). Beginning to offer your best judgments about the future will go a long way in helping patients and families understand what they are facing and hopefully do a better job of preparing for and making decisions about the future.

Image Credit: Trouble with Weather Forecasting by Christian Sinclair for Pallimed / Photo Credit: In the clouds by Kevin Dooley via Flickr Creative Commons
Photo Credit: Amapolas magicas by Jacinta Iluch Valero via Flickr Creative Commons

Pallimed Case Conference Disclaimer: This post is not intended to substitute good individualized clinical judgement or replace a physician-patient relationship. It is published as a means to illustrate important teaching points in healthcare. Patient details may have been changed by Pallimed editors to help with anonymity. Links and minor edits are made for clarity and Pallimed editorial standards.

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by Lisa Podgurski, MD

(Patient information is fictionalized to illustrate this case.)

Case:

Mr. S is a 72-year old man with advanced heart failure and a destination LVAD who was admitted to the hospital for recurrence of VT with subsequent ICD shocks. He experienced several of these shocks during the admission, and had experienced them prior to this hospitalization as well. When Palliative Care was consulted to help manage his anxiety we noted him to be sitting in his recliner very still, avoiding any extraneous movements and telling us about his fear of additional shocks. He also told us that sometimes he wakes at night due to feeling the ICD fire. In the morning when the device is interrogated, there is no recording of a delivered shock. Mr. S mentions a friend who had a similar experience prior to his heart transplant, and his friend sometimes still wakes at night just like Mr. S , even though he no longer has an ICD.

Discussion:

Defining the Problem

Implantable Cardioverter-Defibrillators (ICDs) have a clear role in patients with advanced heart failure whose goals of care include life-prolongation, as a mortality benefit has been shown in large-scale clinical trials. As more patients live with these devices, the psychological effects of having an ICD are being increasingly recognized. The most common forms of psychological distress in patients with ICDs are anxiety (13-38% of patients), depression (18-41%), and PTSD (20%), frequently related to fears of being shocked, whether or not the patient has ever actually been shocked. Effects on body image and on daily behaviors such as physical activities, increased difficulty of screening at airports, and interference with medical care (e.g. MRIs) have also been noted to negatively impact quality of life. Many patients struggle with changing their behavior in an effort to avoid situations they fear will increase heart rate and then lead to a shock, including limiting sexual activity. Although PTSD was previously thought of primarily in cases of combat- or abuse-related trauma, the cardinal features of the condition (vividly reliving an event that was perceived to be life-threatening, avoidance of reminders of the event, and a general state of hyper arousal, all present for greater than 1 month) are frequently seen in patients with ICDs. Predictors of PTSD in these patients include history of more than 5 shocks, younger age, female gender, low social supports, and pre-implantation psychiatric history. A recent study notes a temporal relationship between ICD shocks and subsequent development of anxiety symptoms which was not seen with anti-tachycardia pacing, demonstrating evidence for a causal relationship.

There are some unique features of PTSD in ICD patients, compared with PTSD in other settings. One is the risk of recurrent shock (ongoing trauma), which has prompted a suggestion to re-name the condition “post-ICD shock stress reaction.” Another unique aspect of post-ICD shock PTSD is the phenomenon of phantom shocks, in which the patient feels the experience of a shock without the device actually firing, as occurred in Mr. S and his friend

Strategies for Treatment

A key aspect of addressing the patient’s anxiety and PTSD symptoms is to address the source of the anxiety. Medical strategies for minimizing ICD shocks are essential, including optimization of the patient’s volume status to reduce risk of malignant arrhythmias as well as adjustments to the device to make effective use of anti-tachycardia pacing.

In addition, treatment efforts should include offering the patient coping support and strategies for dealing with shocks. There is solid evidence for the use of Cognitive Behavioral Therapy in this setting. Studies have shown decreased physical limitations, increased physical quality of life, and decreased anxiety. Additional coping tools include relaxation exercises (diaphragmatic breathing, meditation, progressive muscle relaxation) and distraction techniques (imagery, counting, use of a focal point). Patients should be discouraged from avoiding activities they enjoy for fear of being shocked, as this contributes to anxiety and decreased quality of life.

Patient Education

Patient education pages have been developed to help address the psychosocial concerns that develop in people with ICDs including coping strategies for dealing with trauma and stressful events, education on ICDs and sexual health, and support for partners of people living with ICDs. A very helpful one can be found free of charge at http://circ.ahajournals.org/content/127/4/e426.full.pdf. In addition to use of written educational materials, clinical management of all ICD patients should include active screening for PTSD and other forms of psychological distress, anticipatory guidance, and treatment referral.

Conclusion:
Mr. S met with the palliative care psychologist while he was hospitalized and became a frequent-user of deep breathing relaxation techniques. He also employed music as a self-treatment for his anxiety. His wife was able to participate by developing a routine of relaxing things to do in the setting of a threatened or actual shock (e.g. placing a moist towel on his forehead). He planned to connect with a therapist closer to home after discharge from the hospital. In addition to these behavioral coping strategies, he was started on low-dose clonazepam. He was gradually able to tolerate being less confined to a still position in his chair and worked his way up to walking in the hall on the ward. He did continue to experience frequent shocks until undergoing an extensive VT ablation procedure; after this he has had much more infrequent shocks (a few in the next 6 months).

References:
1) Sears SF, Hauf JD, Kirian K, Hazelton G, Conti JB. Posttraumatic stress and the implantablecardioverter-defibrillator patient: What theelectrophysiologist needs to know. Circ Arrhythm Electrophysiol 2011;4:242-250. Open Access

2) Ford J, Sears SF, Shea JB, Cahill J. Cardiology Patient Page: Coping with trauma and stressfulevents as a patient with an implantable cardioverterdefibrillator. Circulation 2013;127:e426-e430. Open Access

3) Schultz SM, Massa C, Grzbiela A, Dengler W, Wiedemanna G, Pauli P. Implantable cardioverterdefibrillator shocks are prospective predictors ofanxiety. Heart and Lung 42 (2013) 105-111.


Pallimed Case Conference Disclaimer: This post is not intended to substitute good individualized clinical judgement or replace a physician-patient relationship. It is published as a means to illustrate important teaching points in healthcare. Patient details may have been changed by Pallimed editors to help with anonymity. Links and small edits are made for clarity and to abide by Pallimed editorial standards.

Photo credit: Implanatble cardioverter-defibrillator by Gregory Marcus, MD, MAS, FACC via Wikipedia CC BY 3.0

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by Julie Childers, MD

(Patient information is fictionalized to illustrate this case.)

Case:
Mr. K is a 88-year-old man with advanced dementia who was brought to the emergency room for agitation and hitting another resident in the dementia unit of his nursing home. This behavior was not new for him. Mr. K, a veteran, spent his time pacing the halls; though he was not oriented, he spoke clearly (frequently about events during the war), ate well, walked easily, and was physically strong. Most of the time Mr. K was calm and could be redirected. However, he occasionally would become agitated and even violent. He would sometimes take his prescribed medications and sometimes refused; when he refused, it was difficult to persuade him and impossible to force him. Multiple medications had been prescribed for his agitation, including lorazepam, risperidone, and olanzapine; none were successful. When he came to the emergency room, he was discovered to have significant urinary retention. Two liters of urine were removed from the bladder, and he became calmer.

Discussion:
More history from the patient’s daughter and the nursing home staff revealed that many of Mr. K’s episodes of agitation coincided with urinary tract infections (UTIs). Among the medications which Mr. K regularly refused was terazosin, prescribed for benign prostatic hypertrophy (BPH). Urinary retention caused by his untreated BPH made him more susceptible to UTIs and also caused pain which he was unable to explain verbally. An indwelling Foley catheter had been previously attempted; however, the presence of the catheter also seemed to cause him distress. How could Mr. K’s symptoms from BPH be treated in a way that would not worsen his agitation?

Background:
The incidence of BPH increases with age, from 20% of 40-year-old men to more than 80% of men over the age 80. Common symptoms are urinary frequency, nocturia, urgency, hesitancy, weak or intermittent urine stream, straining to void, and sensation of incomplete voiding.

There are two main types of medical treatment for BPH: alpha blockers and 5-alpha-reductase inhibitors. Alpha blockers work by reducing prostatic smooth muscle tone and have an immediate effect on urinary flow.

Nonselective alpha blockers (doxazosin, prazosin, and terazosin) can also have systemic side effects, including dizziness, orthostatic hypotension and fatigue. Tamusolin is a highly selective alpha-1A-adrenergic antagonist which avoids these side effects but is more expensive. Studies of alpha antagonists have found an average 25-30% improvement in urinary symptoms.

Five-alpha-reductase inhibitors (finasteride, dutasteride) act by preventing the conversion of testosterone to dihydrotestosterone in the prostate gland, thereby shrinking the gland. Men generally need treatment for 6 to 12 months before the size of the prostate is reduced enough to improve symptoms.


For men with acute urinary retention due to BPH, many urologists recommend a trial of catheterization with use of alpha blockers, followed by attempts at spontaneous voiding. If this fails, transurethral resection of the prostate (TURP) is often performed. This procedure involves the insertion of a scope into the bladder, while the bladder is irrigated; the urologist is able to directly visualize the prostate tissue and resect it piece by piece. The procedure takes 60 to 90 minutes and can be performed under general anesthesia, with a spinal or epidural nerve block or a regional nerve block.

For men who are not candidates for TURP and who have ongoing urinary obstruction, catheterization is an option. A foley catheter can be placed in an office setting, but carries an increased risk of urinary tract infection. Intermittent catheterization can also be used for long term management of urinary obstruction. The final option is a suprapubic catheter, which is placed surgically through the abdominal wall and into the bladder. This reduces trauma to the urethra and the incidence of bladder infection.

Back to the Discussion:
Mr. K’s daughter met with palliative care, psychiatry, internal medicine and urology to discuss the options. Medical treatment for BPH was unlikely to be successful in reducing further episodes. Intermittent catheterization was discussed with urology; however, due to the size of his prostate, catheterization was extremely difficult.

Even if Mr. K would allow it, it couldn’t be done by nursing home staff. TURP might be the most effective treatment for him, but the urologists did not recommend that or any other surgical procedure due to his overall health and his lack of ability to adhere to post-operative care. It was decided to attempt an indwelling Foley again; however, even with the administration of haloperidol prior to the procedure, Mr. C became so distressed and agitated that his daughter asked the urologists to stop.

The next day we met again, and in accordance with Mr. K’s daughter’s goals for her father decided not to attempt further catheterization or to force medications. She thought Mr. K would not want his life extended at all in his current impaired state. We would attempt to reduce Mr. K’s BPH with measures that were not intrusive to him by continuing to offer him alpha blocking medication and a five-alpha-reductase inhibitor, and by discontinuing any medications that could increase urinary symptoms such as diuretics, anticholinergic agents, and tricyclic antidepressants. When he did have agitation we would assume that it was due to obstructive symptoms and would treat the discomfort with sublingual morphine. Eventually we expected that his bladder would become infected leading to sepsis, or urinary obstruction would damage his kidneys and he would go into renal failure. Rather than treating with antibiotics or readmitting to the hospital, we would keep him comfortable in his current setting.

Conclusion:
In this case, a simple condition that is easily treatable in most men became one that we expected to lead to Mr. K’s death. However, the diagnosis that led it to become life-limiting was Mr. K’s dementia, and the heavy burden which BPH treatments would have placed on him.

Mr. K’s daughter based her decision on Mr. K’s values, saying that if the father she was raised by was able to see himself in his current condition, he would have wanted both to stay in place and to be allowed to die with dignity. Forced catheterization and antipsychotic treatment might have prolonged his life by years but would have caused terrible suffering to himself and his family. With the decision to allow his BPH to progress with minimal intervention, we were able to discharge Mr. K to enroll in hospice at his nursing home and completed a POLST form indicating “comfort measures only”.

References:
1.) American Urological Association Guideline: Management of Benign Prostatatic Hyperplasia (BPH) 2010. http://www.auanet.org/education/guidelines/benign-prostatic-hyperplasia.cfm Accessed August 24, 2014.

2.) Burnett AL, Wein AJ. Benign prostatic hyperplasia in primary care: what you need to know. J Urol 2006; 175:S19.

3.) Dull PD, Reagan RW, Bahnson RR. Managing benign prostatic hyperplasia. Am Fam Physician. 2002 Jul 1;66(1):77-85. Open Access


Pallimed Case Conference Disclaimer: This post is not intended to substitute good individualized clinical judgement or replace a physician-patient relationship. It is published as a means to illustrate important teaching points in healthcare. Patient details may have been changed by Pallimed editors to help with anonymity. Links and small edits are made for clarity and to abide by Pallimed editorial standards.

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by Bob Arnold, MD

Case:
It had been a tough day rounding. We had four family meetings one after another. In one, the daughter walked out in the middle because she just could not hear any more. In another, the daughter made it clear that she just was not ready to think about the therapy not working. As we walked to our next meeting, the resident said to me, “Sometimes, I feel that you are too easy on them. Why do you not just tell them that it will not work? They need to understand that the therapy will not work.”

Discussion:
There is a common misperception that conversations about goals of care are always factual conversations. The doctor has to tell the family about the medical condition, the fact that current treatments are not working, and what, if any, options there are. The object of the conversation is to tell the information in a way so that family members “get it” and make “appropriate decisions." Doctors often think that families who do not understand this information are in “denial” or worse, have a financial motive for not understanding what is happening.

In my experience, this is rarely the case. Families often understand the information that the healthcare providers give—they just do not agree with it. (Given that we are giving prognostic information about what is likely to happen in the future, we cannot claim to hold the truth. We are probabilistically more likely to be more accurate, but what the future will bring is, until it occurs, unknown.)

Instead these conversations are about loss, sadness and anxiety. Loss about the current treatment not working. Sadness that the patient will not be able to achieve the goals they were hoping for. Anxiety about what the future might bring. Until these emotions are heard, acknowledged and processed, it may be hard for family members to move onto the next step—thinking about what their loved one would say given the new medical situation.


What data do I have for this belief? The family says things like “I know, but we cannot stop hoping,” or they just keep wondering if there is not something else that might work, or they hope for a miracle (which by definition means they know that what we are doing is not working). In these cases, the family does understand what clinicians are saying—they just do not agree with it, do not want it to be true or cannot imagine the consequences if our view of the future proves true. Trying to convince the family that our view of the future is the correct one often leads to conflicts where we are repeatedly giving bad news, the family keeps wondering or demanding something else, and we all leave unsatisfied. The family feels like we are giving up, and we feel like they “do not get it.”

There is another way to think about how to have these conversations. Think about them occurring on two planes—a factual plane and an affective (or emotional) plane. Typically we operate on the factual plane where we try to convince the family that our view of the future is the correct one. The problem is that what is happening on the emotional level precludes family members from cognitively processing and using this information. Psychologists know that we do not process cognitive information when we are emotionally flooded. In addition, when the information is too painful, one may actively resist acknowledging it because it is too painful (“denial”).

In addition, family members’ emotional reactions tell us about what is most important for them at this time. It gives the clinician a window into the things that the family is most concerned about, cares about and is worried about.

Finally, these emotions are normal when someone is being asked to confront or see something that they do not like. The fact that the family is having these emotions is, in fact, pretty good evidence that they do understand what you are saying, and they do not like it. Rather than trying to convince them on the factual plane that you are right, it will lead to a healthier relationship and better conversations if you meet them on the affective plane.

What does this mean for the clinician? It means, rather than giving information, attending to family members' emotions. It means acknowledging that “this is scary,” or that things are not going the way that they want. It means not fighting with them about the facts about what might happen and joining them on the emotional plane: This is not what we wanted to have happen, and, in fact, there is a part of us who, like them, wishes the better story would come true.

When people feel heard and appreciated, their emotions often decrease making them more able to think through the facts. They are able to think about situations that otherwise would be too frightening, scary or sad. They can begin to consider what their loved one would say about this new situation.

Conclusion:
I know this is a long answer to my resident’s question, probably more information than he or you wanted. So I will end with a suggestion: If it feels like the conversation you are having with the family is a battle, if it feels like they are not listening to you or do not want to attend to what you are telling them, or they keep asking the same questions, think about what the affective plane of the conversation is. Try to identify the emotions that the family is expressing and see if you can acknowledge or name the situation for them. Stop trying to convince them and try to join them on that plane to see if you can help move the conversation from a fight over who is “right” to jointly confronting the situation they are facing.

Acknowledgement:
Thanks to Debbie Seltzer for her editing and Tony Back, James Tulsky and Kelly Edwards (Vitaltalk.org) for helping me realize this and figure out how to teach about it.


Pallimed Case Conference Disclaimer: This post is not intended to substitute good individualized clinical judgement or replace a physician-patient relationship. It is published as a means to illustrate important teaching points in healthcare. Patient details may have been changed by Pallimed editors to help with anonymity. Links and small edits are made for clarity and to abide by Pallimed editorial standards.

Image: iStockPhoto

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Case:
Ms. Turner* is a 29-year-old woman with recently diagnosed ovarian cancer discovered after presenting to the ED with worsening abdominal pain. CT imaging showed a 4.8cm cystic mass extending from her right ovary, and the surgical pathology revealed ovarian adenocarcinoma. Two weeks post-operatively, she was hospitalized for initiation of chemotherapy, and the palliative care service was consulted for symptom management. Despite having received treatment with ondansetron (Zofran®), aprepitant (Emend®), dexamethasone (Decadron®), lorazepam (Ativan®), and haloperidol (Haldol®), she developed significant nausea and vomiting on the first day of chemotherapy infusion with symptoms worsening on her second day of chemotherapy. She described feeling utterly miserable and fearful about her next chemotherapy infusion, and she was continuing to experience nausea and repeated episodes of emesis overnight with minimal oral intake. Ms. Turner also described an underlying history of anxiety disorder predating her cancer diagnosis. At home she typically smoked marijuana on a daily basis to help manage her anxiety symptoms, which she reported did not interfere with her successful function at work and school. On review of systems, she noted abdominal discomfort for which she was taking low dose oxycodone and that she had not moved her bowels for several days.
Discussion:
Nausea and vomiting (NV) are commonly reported side effects with chemotherapy.¹ The primary pathway for NV involves the chemotherapy drugs directly stimulating the chemoreceptor trigger zone (CTZ), in the area postrema at the base of the fourth ventricle. Activated receptors in the CTZ transmit signals to the vomiting center in the brainstem to produce NV. Receptors in the CTZ include serotonergic receptor 5-hydroxytryptamine type 3 (5-HT3), dopaminergic (D2) and neurokinin type 1 (NK-1) receptors. In addition, chemotherapy can damage GI mucosa causing local release of 5-HT3 neurotransmitters by gut enterochromaffin cells, activating peripheral pathways along the vagus and splanchnic nerves and directly triggering the vomiting center. Finally, chemotherapy-associated anxiety may also stimulate the vomiting center through central cortical pathways. Whether transmitted via signals from the CTZ, the cortex, or peripheral inputs, the vomiting center has several different receptors involved in initiating the vomiting reflex: muscarinic acetylcholine (Achm), histamine type 1 (H1), and 5-hydroxytrypamine type 2 (5-HT2).¹

Given the pathways for chemotherapy-induced nausea and vomiting described above, 5-HT3 and NK-1 receptor antagonists such as ondansetron and aprepitant, in combination with dopamine antagonists such as haloperidol, are typically effective for treatment of NV. In some cases, however, patients may develop breakthrough nausea and vomiting despite adequate standard therapy requiring additional or alternative anti-emetic medications. According to guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network, there are several categories of second-line agents that may be useful in refractory cases.^2,3

The cannabinoids dronabinol (Marinol®) and nabilone (Cesamet®) are both FDA approved for refractory chemotherapy-induced nausea and vomiting.⁴ Unlike other anti-emetic medications which block receptor activity for their therapeutic effect, cannabinoid effect is exerted by agonist activity on the cannabinoid receptor in the brain CB1.⁵ Dronabinol is a Schedule 3 synthetic THC (delta-9 tetrahydrocannabinoid). Starting dose is typically 5mg 2 hours prior to chemotherapy and every 4 hours as needed, with a maximum dose of 15mg. Nabilone is a Schedule 2 drug with longer onset and duration of action, and is dosed 1-2 mg twice or three times daily as needed. Studies demonstrate that dronabinol and nabilone are effective for treatment of nausea and vomiting; however, their use is limited by their side effect profile including vertigo, xerostomia, hypotension, dysphoria, and hallucinations.^4,5

Olanzapine (Zyprexa®) is an atypical antipsychotic which antagonizes multiple neurotransmitters including dopamine at D1, D2, D3 and D4 brain receptors; acetylcholine at muscarinic receptors; serotonin at 5-HT2, 5-HT3, and 5-HT6 receptors; catecholamines at alpha-1 adrenergic receptors; and histamine at H1 receptors.⁶ Several studies have demonstrated its utility for treating chemotherapy-induced nausea and vomiting.⁶ No studies have specifically compared it to haloperidol or other atypical anti-psychotics for treatment of nausea, although several authors have argued that it is the multiplicity of olanzapine’s receptor activity which contributes to its effectiveness. The recommended dosing is 5mg orally daily starting 1-2 days before chemotherapy, then 5-10mg daily for days 1-4 of chemotherapy. Side effects include sedation, dry mouth, increased appetite, hyperglycemia and postural hypotension.^2,3

Metoclopramide (Reglan®) has central and peripheral anti-dopaminergic activity, and at high doses also exerts 5-HT3 antagonist effect which is thought to contribute to its anti-emetic effect.1,2 Because of its low therapeutic index, metoclopramide is typically reserved for patients who are intolerant or refractory to first line anti-serotonergic agents. Dosing is 10-40 mg IV 30 minutes prior to chemotherapy, then every 4 to 6 hours as needed.³ An alternate dosing strategy is 1-2 mg/kg 30 minutes before chemotherapy and then repeated 2 hours after chemotherapy for 2 doses, and then every 3 hours for 3 doses. Side effects include dystonia, akathisia, sedation, and esophageal spasm. Pretreatment with diphenhydramine (Benadryl®) will decrease risk of extrapyramidal reactions.²

Benzodiazepines are most useful in cases of anticipatory NV, which is thought to be a conditioned reflex as a result of prior poor control of emesis during chemotherapy treatment.³ The phenomenon involves the development of NV when a sensory stimulus (ie, the sights, sounds, or smells of chemotherapy clinic) becomes paired with the experience of symptomatic chemotherapy treatment. After a conditioning period (ie, repeated chemotherapy infusions in clinic), the sensory stimulus or anxiety from negative anticipation may trigger NV before the patient has even received the chemotherapy infusion.⁷ The mechanism involves signals along intracerebral projections in the cortex directly stimulating the vomiting center. Older studies had described the phenomenon in up to 25% of patients with poorly controlled symptoms by the fourth treatment cycle; however, the frequency appears to have decreased with the advent of more effective anti-emetic regimens. Patients with refractory NV are at higher risk of developing anticipatory NV. The intermediate-acting benzodiazepine lorazepam is helpful for treatment of anticipatory NV and as an adjunct in cases of refractory NV, with starting doses of 0.5-1mg oral or IV, and up to 2mg, every 6-8 hours as needed for anxiety and nausea.⁷

Resolution of the Case:
Based on her symptoms and previous history, Ms. Turner was started on dronabinol 5mg three times daily during her chemotherapy treatment while in the hospital, along with the scheduled ondansetron and haloperidol. A bowel regimen of senna (Senekot®) and polyethylene glycol 3350 (Miralax®) was also initiated, as opioid-induced constipation was likely contributing to her symptoms. Within 24 hours, she had resolution of emesis and improvement of her nausea, enabling her to resume oral intake.

Summary:
While standard anti-emetic therapies with 5-HT3 and dopamine antagonists are effective and well-tolerated in most cases of chemotherapy-induced nausea and vomiting, occasionally refractory symptoms necessitate addition of a second-line agent such as a cannabinoid, olanzapine, or metoclopramide. Patient characteristics such as age, previous experience with cannabinoids, and medical comorbidities will impact the choice of second-line agent. Dronabinol or nabilone may be most effective in younger patients and those with previous experience of tolerating cannabinoids. Olanzapine is preferable in elderly patients or populations for whom there may be a concern about the psychoactive properties of cannabinoids. Substitution of high dose IV metoclopramide for other dopaminergic and 5-HT3 medications could also be helpful in certain cases, especially if there are additional concerns about GI dysmotility or intolerance to standard 5-HT3 agents.

References:
1. Wood G, Shega J, Lynch B, Von Roenn J. Management of Intractable Nausea and Vomiting in Patients at the End of Life. JAMA 2007; 298(10): 1196-1207.
2. Basch E, Prestrud AA, Hesketh PJ. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2011; 29:4189. Open Access PDF
3. Hesketh PJ. Chemotherapy-Induced Nausea and Vomiting. N Engl J Med 2008; 358(23):2482-94.
4. Wilner LS, Arnold R. Cannabinoids in the Treatment of Symptoms in Cancer and AIDS, 2nd edition. Fast Facts and Concepts. December 2007; 93.
5. Todaro B. Cannabinoids in the Treatment of Chemotherapy-Induced Nausea. J Natl Compr Canc Netw 2012; 10:487-492.
6. Nizukami N, Yamauchi M. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting in Patients Receiving Highly or Moderately Emetogenic Chemotherapy: A Randomized, Double-Blind, Placebo-Controlled Study. Journal of Pain and Symptom Management March 2014; 47 (3)542-550.
7. Roscoe J, Morrow G. Anticipatory Nausea and Vomiting. Support Care Cancer Oct 2011; 19 (10): 1533-1538. Open Access PDF


Pallimed Case Conference Disclaimer: This post is not intended to substitute good individualized clinical judgement or replace a physician-patient relationship. It is published as a means to illustrate important teaching points in healthcare. Patient details have been changed by Pallimed editors to help with anonymity. Links and small edits are made for clarity and to abide by Pallimed editorial standards.

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Discussion:

Everyone has a story to tell.  This is a basic summary of legacy project’s purpose.












Pallimed Case Conference Disclaimer: This post is not intended to substitute good individualized clinical judgement or replace a physician-patient relationship. It is published as a means to illustrate important teaching points in healthcare. Patient details have been changed by Pallimed editors to help with anonymity.