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Robin Williams’ death prompted a small flurry of tweets and articles looking for more awareness of and attention to mental health. Earl Quijada (@equijada) and I had a short exchange that really got me thinking about how we view mental illness in the medical world. Our palliative care team cares for a fair number of patients with serious medical illness (cancer, heart failure, etc) who also have serious mental illness (SMI) such as profound depression, bipolar disorder, schizophrenia, etc. In my experience, there are unique challenges to providing the best care to these patients for both their health-care providers and their loved ones. Additionally, it seems likely that these patients experience the medical system in a way that is different and perhaps more challenging to them personally than patients without SMI, creating the potential for suffering.

With those thoughts in mind, here are the topics for discussion for this week’s #hpm Tweetchat:

1. How does the medical establishment care now for patients with serious mental illness(SMI)?
2. What role does palliative care have in improving the care of patients with SMI?
3. What challenges do we perceive for providing palliative care in patients with SMI? What opportunities exist?
4. Should palliative care consultation be part of the routine care for patients with SMI?

What: #hpm Tweetchat
When: Wed 8/27/2014 - 9p ET/ 6p PT
Host: Dr. Meredith MacMartin
Facebook Event Page: https://www.facebook.com/events/276720409189081

After the chat, we will post the transcript and analytics here.

For more on #hpm Tweetchats see our archive of transcripts and analytics, and other Twitter-related posts here on Pallimed.
For more posts on psychiatry on Pallimed, click here.

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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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You will often hear the lament from people within and outside of the hospice and palliative care fields, that doctors are pretty bad at making effective prognostication. Patients and families frequently search for a predictable road map to understand the course they are likely on, and even when they cede the understandable uncertainty to the physician, the doctors will often reply with an unhelpful retorts like, “I don’t know what may happen. There is only one person who does.”

I doubt all of those physicians are referring to Dr. Mark Cowen, but they may want to take notice of what he and his colleagues at St. Joseph Mercy Hospital in Ann Arbor, Michigan have been doing for the past couple of years. Having already developed and validated a 30-day mortality prediction rule (MPR) (published in 2013), the team now advanced the idea to a prospective, real-time mortality prediction rule study. Published online in the Journal of Hospital Medicine this month, “Implementation of a Mortality Prediction Rule for Real-Time Decision making: Feasibility and Validity” may help clinicians move from pre-contemplation to contemplation when it comes to applicable prognostication.

The MPR in this study was completed on almost 10,000 patients admitted to the hospital (78%) and an outpatient surgery center (22%) at a tertiary community teaching hospital over the Fall 2012 to Winter 2013 (yup, flu season!). Some high mortality risk (dialysis units, transfers from outside hospitals) and low mortality risk admissions (child birth/OB) were not included, most likely because the ability to implement the rule before having a bed assigned was more challenging to accomplish. Since this is not only a validity study, but also a feasibility study, they nicely discuss the diplomacy, champion-finding, and need for paid support staff for this project to work. Interestingly, the authors note the ED staff were open to this prediction rule only if they could accomplish the task “within the time a physician could hold his/her breath.” Be careful what you say in a research administrative meeting, you may see those words published in a journal article some day!

The rule was Web-based and pre-populated data from the EMR without any manual effort. Updates were done to the Web-based rule as often as every minute! Then ED doctors or surgery center nurses reviewed the pre-populated information and made overrides if necessary. Samples of the questions asked include:

History or presence on admission of:

• Atrial fibrillation
• Solid-tumor cancer
• Metastatic cancer
• Cognitive deficit
• Leukolymphoma
• Other neuro deficit

Patient’s current condition/treatments:

• Respiratory failure
• Heart failure Injury
• Sepsis
• Abnormal vital signs

At first the clinicians did not have access to the score but that changed over the course of the study, which to me is one of the weaker parts of the study. It treats this whole group as one, but really this is equivalent to having a study where you have blinded the clinicians and the patient, and then midway through you started to un-blind some of them as to the treatment/test/intervention. The authors talk about two care processes put in place as these scores became available which may impact the true validity of this MPR de novo. Wouldn't it make more sense to test this MPR without changing any behavior (via knowing the score), and then test how it could impact clinical delivery and patient outcomes? The impact of this MPR was a slight bit muddled because of that contamination of the study population.

They split the population into 5 risk categories by quintiles, with the highest risk population having an approximate 7-35% chance of 30d mortality.

But let’s get to the real meat of what Pallimed readers care about, did this study group look at palliative care consults, or hospice utilization? Sorta, kinda. We're going to need to do a little hypothesizing and I will expand on that in an upcoming post. We will talk about what an accurate MPR could do for palliative care and hospice utilization.

Of note, nurses worked with this tool, so if anyone says that prognostication is not the role of a nurse, you can point them to this article.  Nurses should not be excluded from prognostication based on credentials. I appreciate when nurses give me an honest assessment of prognosis, and I hope other doctors out there do as well.

Some other information that would be really helpful is understanding the outliers in the high risk strata.  Who were the people who lived but were high risk? And for how long? Do they have any significant quality of life issues post-hospitalization?

Other info that would be great to see is how much overlap there was in the different groups. For example, if you had palliative care while in the hospital, what was your likelihood of a 30d readmission.

So overall, this is a really good study, and is very accessible in the way it is written. Since it is published in a non-core HPM journal it should be quite easy to approach your hospitalists and ED colleagues to talk about possibly doing a validation study in your local hospitals.

Credits: Future Road Sign - iStockPhotos; Quote - Illustration by Pallimed; Chart - From article under Fair Use guidelines for for nonprofit educational purposes. Full copyright of that figure is retained by the journal.

Cowen, M., Czerwinski, J., Posa, P., Van Hoek, E., Mattimore, J., Halasyamani, L., & Strawderman, R. (2014). Implementation of a mortality prediction rule for real-time decision making: Feasibility and validity Journal of Hospital Medicine, Early Publication DOI: 10.1002/jhm.2250

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If you’ve ever helped as a caregiver to someone in the twilight years of their life, or perhaps you yourself are at this stage, you may have noticed when it was medication time that there were a lot of pills. It is true there are exceptions to this rule, those individuals who only take one or two medications a day. However this is the exception, and there doesn’t seem to be much middle ground. Either you are on pages worth of medication, or hardly any as you begin to enter the last stages of life.

The first question is, how does this happen? A large culprit to this phenomenon stems from the expectations for the doctor/patient encounter. When a patient comes to see a provider with a specific complaint, they expect a remedy. The unspoken words from every patient are “fix me”. While most complaints aren’t easy to alleviate quickly, culture demands instant relief. Thus, handing out a new medication for a complaint certainly feels like the problem has been addressed. This is not much different to what happens when my 3 year old skins his knee. He has been enculturated to believe that with any scrape a Band-Aid is the ultimate solution. As a parent, I can tell that most of his injuries medically don’t need Band-Aids, and yet when I relent I’m amazed at the immediate soothing effect it has because something has been done to “fix” him. Medications at times are like Band-Aids, they may not be essentially needed, but we expect something from them, and so in turn, they pacify us.

The next issue with medications is the tendency that once started they are never stopped. Someone comes into the hospital for knee surgery and complains of indigestion due to anxiety about the surgery, so an antacid is prescribed. The person is discharged with the new medication, and years later are still taking it, despite not medically needing it. When I put a Band-Aid on my 3 year old, it takes some convincing after a day that I can remove it, because he is now healed. How funny it would be if we left Band-Aids on indefinitely, never evaluating if the injury healed. Yet this is often the case for pills, started by other specialists, or for specific reasons in the past, we trust their benefit, like the Band-Aid, without pondering if still needed.

When it comes to end of life, the harm of over prescribing and not eliminating medications is something called ‘pill burden’. Patients fatigued from their disease and having more difficulty swallowing become burdened by the handful of medications we expect them to take. Many pills can be eliminated because of the above scenarios, but even more can be stopped when we evaluate why someone is taking the pill in the first place.

Many medications prescribed are preventative, meant to stave off unwanted future risks. Some of these drug classes are blood thinners, cholesterol lowering agents, blood pressure medications, dementia medications, and all vitamins. These agents are meant to prevent things years in the future, so it makes no sense continuing them on hospice when time is limited.

Pill burden doesn’t just occur at the end of life. It’s okay to be an advocate and sit down with your physician to discuss the necessity of medications prescribed. The key is to ensure the pills you take are working for you, because it can be work to take them in the first place.

Dr. Clarkson is a hospice physician for Southwind Hospice in Pratt, KS. This post was originally published in Dr. Clarkson's End Notes column for the Pratt Tribune.  It is re-published here with the author's permission under a Creative Commons license.

Photo Credit: iStockphoto

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(Welcome a new contributor to the Pallimed Blog! Lizzy Miles, MA, MSW, LSW is a hospice social worker in Ohio who has also contributed to the Pallimed: Arts and Humanities site with a post on bucket lists in a Smurfs game. Yes, you read that right. She is best known as the the person who brought the Death Cafe concept to the US. We are very excited to be working with Lizzy! - Ed.)

Photo Credit: Emily Riegel

Lizzy Miles, MA, MSW, LSW is a hospice social worker in Columbus, Ohio and author of a book of happy hospice stories: Somewhere In Between: The Hokey Pokey, Chocolate Cake and the Shared Death Experience. Lizzy is best known for bringing the Death Cafe concept to the United States. You can find her on Twitter @LizzyMiles_MSW 

Note: This article was later expanded into a series of seven additional articles. The next article in the series is a detailed look at the first assumption: How Assumptions about Dying Can Negatively Affect Patient Care.

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