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We welcome comments about any aspects of the questions or the answers/discussions.  The feedback that we hope to get in the comment sections of the post will help us all learn important aspects for the boards. We also welcome an interdisciplinary viewpoint when answering these questions, so even if you are not taking the medical boards, your input is still very much welcome.

Walking into a room at your hospice inpatient unit you see a tired appearing female patient lying in bed with soft moaning, holding her abdomen. She has end stage CHF and no history of cancer. Review of your notes show decreasing oral intake and increased time in bed. Her nurse reports she disimpacted her yesterday after suppositories and enemas were ineffective for worsening constipation.

Medications include: Fentanyl 50mcg patch (on for several weeks), Senna 2 tabs BID, Colace daily, Recent enema, and docusate suppository
Exam: Cachectic female, Scaphoid abdomen, hypoactive bowel sounds, formed (but not hard) stool on rectal exam.

What is the next best step?
a) Write an order for methylnaltrexone 8mg subcutaneously x1 now.
b) Switch her from a fentanyl patch to a morphine pump so you can better manage her abdominal pain.
c) Write an order for octreotide 200mcg subcutaneously twice daily for three days.
d) Place an NG and give her polyethylene glycol daily until she has a bowel movement or regains ability to swallow and you can remove the NG tube

Discussion:Show/hide Discussion

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Earlier this month the 2011 ACP annual meeting was held in San Diego.  In addition to escaping New England to Southern Cal in early April, I got to see old friends at San Diego Hospice, meet the fellows, and catch some pearls at the ACP meeting.  I wish there were more of us there tweeting and blogging, because I could not catch all the talks I wanted to.  Here are some of the articles highlighted in talks I attended that may be pertinent to our field:


Updates of Ethics, Dr. Sha reviewed key articles/events in palliative care and ethics:

• The CDC takes a stand on distributive justice during influenza pandemics in allocating ventilatory support to patients. - Article: Manuel ME Pandemic Influenza: Implications for Preparation and Delivery of Critical Care Services J Intensive Care Med. Jan 10, 2011 doi:10.1177/0885066610393314 
• Medical students who reflect, debrief with faculty about a death they experience, show more empathy and professionalism. - Kelly E, Nisker J. Medical students' first clinical experience of death. Med Ed 2010 
• Challenging autonomy in medical decision-making in critical care settings - some advocate for increased beneficence to ameliorate the distress of surrogate decision-makers. - Curtis JR, Vincent JL. Ethics and End-of-Life care for adults in the intensive-care-unit. The Lancet, Oct 2010. doi: 10.1016/S0140-6736(10)60143-2 
• Can we help the homeless complete advance directives? A study by Song and colleagues say yes! Song J, et al. Effect of an end-of-life planning intervention on the completion of advance directives in homeless persons. Ann Int Med. 2010;153:76-84.
• Other references:
• Laurey S, et al. Unresponsive wakefulness syndrome: a new name for the vegetative state or apallic syndrome. BMC Medicine. 2010; 8:68
• Powell T. Life imitates work. JAMA 2011; 305:542-43.

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Looking for a medication that can reduce a troubling symptom in an advanced disease and reduce hospitalization? Sound like the "perfect" palliative care drug? Read on and decide...

NEJM published a randomized controlled trial comparing the antibiotic rifaximin at 550 mg po bid versus placebo for the prevention of recurrent hepatic encephalopathy. While other studies have suggested that rifaximin might be beneficial in treating hepatic encephalopathy, they have all been small studies of short duration and looked at the treatment of HE rather than prevention.

More than 90% of patients in both wings received concurrent lactulose therapy. Subjects were followed for six months with the primary endpoint being the time to the first breakthrough episode of hepatic encephalopathy. A major secondary endpoint was the time to rehospitalization. Patients with the most advanced disease were excluded (MELD score greater than 25 and the presence of several other complications such as creatinine greater than 2.0 g/dl). The study was funded by Salix Pharmaceuticals, the makers of rifaximin.

The results:

• Breakthrough episodes of hepatic encephalopathy were reported in 31 of 140 patients in the rifaximin group (22.1%) and 73 of 159 patients in the placebo group (45.9%). The hazard ratio was significant at 0.42. The number needed to treat to prevent one episode of HE is 4.2.
  
• Hospitalization involving hepatic encephalopathy was reported for 19 of 140 patients in the rifaximin group (13.6%) and 36 of 159 patients in the placebo group (22.6%). The hazard ratio is reported as 0.5 and the relative risk reduction was reported as 0.5 as well. However, based on my calculation, the relative risk reduction is closer to 0.4. They report a NNT of 9. I calculate a NNT of 11.
  

6.4% of patients in rifaximin group died in the six month period vs. 6.9% in placebo group. Rifaximin was generally well tolerated. Two patients in the study group developed Clostridium difficile versus none in the placebo group.

The authors point out potential downsides to alternative antibiotics, including neomycin. Oral neomycin can cause ototoxicity, nephrotoxicity, and peripheral neuropathy. (According to Lexicomp, this risk is less than 1% but there is a black box warning.) Metronidazole use may be limited by nausea and peripheral neuropathy.

While I don't prescribe neomycin for hepatic encephalopathy typically, there have been two previous clinical trials comparing rifaximin to neomycin. One showed no significant difference between the two over 21 days. Another showed a small advantage to rifaximin that was statistically insignificant. I've read several recommendations against neomycin because, in addition to the potential toxicity, there is clinical trial data suggesting that it is no better than placebo, but that's based on one clinical trial in patients who had acute encephalopathy where the neomycin group resolved within 40 hours compared to placebo 50 hours (not statistically significant).

I couldn't find any other trials head to head of rifaximin versus other therapies. Metronidazole and vancomycin don't appear to be well studied in general (although the former seems to be the most commonly used secondary agent behind lactulose).

After reviewing other studies, I wish there were a wing of this study for at least one of these agents. All are significantly less expensive and it would be nice to have a better understanding of the toxicity in a larger trial in this population. The "risk" for including one of these agents in this industry funded trial would be that the agent might work and not be as toxic as everyone thought it might be.

All of that aside, hepatic encephalopathy and the associated need for hospitalization can be a major burden for patients with advanced cirrhosis and their families. The study excluded the sickest patients (the ones most likely to be seen by palliative care or referred to hospice). But while it may be difficult to know how these results apply to a sicker population, it seems plausible that they can be extrapolated. Anything that reduces the incidence of encephalopathy or hospitalization is appreciated, but because of the cost, it makes sense that it should still be reserved for those with recurrent encephalopathy. And if started, one should monitor for the expected endpoints and discontinued if no improvement is seen. One could argue that other antibiotics should still be given a trial, as well- I'm not convinced that this trial knocks other antibiotics out of the "on-deck" circle behind lactulose. Look for a jump in the use of this medication because of this study and the lack of data behind other agents, though. Rifaximin now has FDA approval for this indication.

If rifaximin use does become more commonplace, it will be interesting to note how hospices handle the drug. While reducing hospitalization is always a good thing and may potentially save the overall health system money (maybe even a LOT of money, if you agree with this study), a hospice that is reimbursed on a per diem basis might struggle to cover this expensive medication (especially since the average patient with refractory encephalopathy may have more days to spend at home while taking this drug!) This type of therapy can be a real pickle for hospices- proven to benefit, palliative only, and expensive.

Even though it may be possible to extrapolate the results of this study to a population with more advanced liver disease, I don't think this study demonstrates any role for patients with a very limited prognosis (days to weeks).

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As I mentioned in a recent post I have accumulated a large back-log of articles to discuss, and so am going to do a few weeks worth of quick-n-dirty article commentaries to catch up.

And so here it is, the 2nd Annual Palllimed Autumn Mag Citrate Bonanza (in reverse chronological order going down my pile):

1)
Medical Decision Making has a study exploring patients wanting chemotherapy and hospice at the same time. It is reminiscent of research we discussed here. This study is based on a survey of smokers (not actual lung cancer patients, and who had a median age of 34 years) and asks them a series of hypothetical questions (essentially if you had incurable lung cancer, and these were the options presented to you, which would you prefer). They were given accurate, albeit simplistic, descriptions of ‘supportive care,’ chemotherapy, hospice care, and hypothetical combinations of those. Basically most subjects responded that they’d prefer chemotherapy and hospice at the same time. This should not be surprising since essentially what they were choosing in this research was 'The Most Care/Win Win' option (treatments to prolong their life, to attenuate chemo side effects and cancer symptoms, and added practical/emotional/spiritual support to boot). Sounds pretty good when the alternatives were not having one of those benefits, and I’m not sure extrapolating from this young/healthy population’s choice of More Help over Less Help particularly adds anything to our understanding of barriers to hospice care.

Which is not to say they’re wrong: having to forswear chemotherapy is a barrier, but a complicated one, and doesn’t answer the question as to whether we want hospice per se to be able to do everything for those with short prognoses (see related post link above). That is, I think part of this research seems to be rooted in the idea that as a society/medical system if someone has a short prognosis (less than 6 months) they should be in hospice and it's a major problem that so many aren't. I'm personally not sure that this is the case (hospice is underutilized, majorly, to be sure) - they should be offered hospice, they should be receiving superb palliative care (whether or not from a palliative specialist), and they should not be offered ineffective, burdensome treatments: 'The Problem' is that patients aren't getting this anywhere nearly as often/much as they should be. This is different from them 'needing' hospice, and that the 'fix' is just getting these patients into hospice. If we advocate for a system in which patients can receive ineffective, burdensome treatments plus hospice care to soften the blow - we aren't doing anyone a big favor.

(Thanks to Dr. David Weissman for alerting me to this article.)

2)
NEJM has a tidy review of renal failure in cirrhosis. It discusses, generally, its pathophysiology and treatment, and the role of liver and kidney transplantation in its management. While not - at all - palliative oriented, it does touch on prognosis, as well as provides a concise summary of the approach to this highly mortal situation that is not uncommonly seen by palliative clinicians at hospitals which manage these patients (ie – a nice brush-up article for the teaching file). The prognosis data are dismal: this article argues for a 50% 1 month and 20% 6 month survival for patients with cirrhosis and renal failure (without transplant). Yikes.

3)
On the social media & medicine side of things, JAMA just published a survey of medical school deans asking about concerns/history with inappropriate content posting to social media sites by medical students. It seems it is indeed an emerging problem. While a lot of the problem seems to be students whining and revealing themselves in undignified situations (drunk/suggestive party shots, etc.), there were also problems with posting confidential patient material (an issue more of a concern to medical bloggers and why we have tried to be very strict about this on our blog). Most of the reports to deans about this were from within the medical school (staff, other med students, etc.) and only 4% were from patients/families themselves.

4)
Social Sciences & Medicine has a qualitative study using grounded theory about the desire for hastened death (DHD) – based on extensive 1 on 1 interviews with 27 adults with advanced cancer at a cancer center in Toronto, all of whom endorsed some contemplation of a wish for a hastened death. These were sick patients – 70% died during the course of the study. The themes that emerged are consistent with what I think many of us who work with dying patients hear frequently. They found that DHD clustered around 3 themes: a hypothetical exit strategy if things get rough; an expression of despair, and a more peaceful-or-at-least-resigned, ‘letting go’ meaning. None of these themes and the quotes they give really are consistent with suicidality – these patients who expressed, at times, DHD, were not suicidal, at least in the way we usually think about suicide (that is – really/truly wanting to be dead; instead the patients wanted to feel better or, as they resigned themselves to the inevitable, had times when they wondered to themselves that given this was actually going to happen anyway why wait around).

It’s a fascinating read, if nothing for the quotes from patients and to hear what they go through (and the things that others put them through):

“I've experienced such incredible pain over the last little while and more in the last week. Such incredible pain that it made me think that death is preferable to this…I'll sit there for 2 hours in terrible pain. Such pain where I can't yawn even, and I get only half a yawn and my whole insides turn and waiting for the medication to start to work…I'd love to have 48 hours let's say, I'd love to have this weekend where I could plan to have a nice weekend and have no pain. I'd love to do that and it doesn't happen, and the pain affects everything. It makes you tired. It affects how you can eat. It affects your mood. It affects other people, and the fact is that even if you try to hide it, you can't… So that's hard…and I know it's gonna get worse, so that's hard too. It's great to be alive, and pain takes that life out of you, and to sit there for 2 hours with a blanket around you just shivering, with no solution, is really hard.”

“I find it difficult. The two extremes, where the people who tell me that I'm not going to die because God is good, and that God will save me in a miracle, and I say ‘God is good and sometimes He will save people in miracles. But if it was something that would happen to me – it would have happened already. So we have to accept the fact that there is no miracle here…that my time is over.’ And I also find it very hard, the other side, where I ‘love’ the people who constantly say there's nothing wrong with me, everything will be fine, because there is something wrong with me and everything will not be fine."

5)
PLoS Medicine has a study about ‘prolonged grief disorder’ (aka ‘complicated grief’) which tries to validate proposed diagnostic criteria for PGD for the DSM V. The data come from the Yale Bereavement Study (which also generated this controversial and misunderstood JAMA paper about the stages of grief) and involved interviewing bereaved adults (~300, mean age 61 years, interviewed on average 6, 11, and 20-months post-loss).

This is a complicated, statistics-heavy paper (involving how they developed and validated the diagnostic criteria for PGD based on their data set) and I’ll freely admit it broke my brain reading it; this is to say that I can’t comment personally about how persuasive, or not, their proposed criteria are (an accompanying editorial is supportive however of the findings). It's a revealing insight for the uninitiated into how these new diagnoses get established.

The proposed criteria call for diagnosing PGD after 6 months post-loss, and the symptom criteria (you can read in the paper – Table 3) include yearning and the following other symptoms (and in usual DSM style, noting that these cause significant impairments, are not better explained by another disorder, etc. etc.).

1. Confusion about one’s role in life or diminished sense of self (i.e., feeling that a part of oneself has died).
2. Difficulty accepting the loss.
3. Avoidance of reminders of the reality of the loss.
4. Inability to trust others since the loss.
5. Bitterness or anger related to the loss.
6. Difficulty moving on with life (e.g., making new friends, pursuing interests).
7. Numbness (absence of emotion) since the loss.
8. Feeling that life is unfulfilling, empty, or meaningless since the loss.
9. Feeling stunned, dazed or shocked by the loss.
   

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We don't typically endorse products, webinars, conferences, job listings or much of anything else here at Pallimed, but when we do know about a resource that can impact your everyday palliative care work we want you to know about it.

Such is the case with the Hospice and Palliative Care Formulary USA ($75/$65 for AAHPM members) now being published in the 2nd edition from the founders of PalliativeDrugs.com, Robert Twycross and Andrew Wilcox.  I wanted to write in more detail about why I access this book more often than any other palliative care book since I just ordered 6 of them for the teams I work with.

The first edition was printed in 2006 and my copy is dog-eared from carrying it around, showing it to hospice team members, lending out to fellows, residents, nurse case managers, copying a page for a pharmacist, referencing it for numerous presentations, etc.

Any other medication reference book (nursing or medical) has so many warnings/misinformation about the medications we commonly prescribe and administer in palliative care settings that general pharmaceutical reference books are essentially useless.  I often find nurses and physician trainees who read some of those freebie/cheap Nursing/Medical Drug Guides begin to contradict basic palliative care understanding.

For some poor examples from referencing other drug guides...

"We can't give more than 5mg of morphine...the book says she might have respiratory depression."
"Octreotide? I don't see anything about small bowel obstruction but it does treat a VIPoma."
"Constipation? How about we try more fiber?"

Here is why I find HPCF-USA so useful:

• Detailed palliative care oriented medication information
• Extremely well referenced drug monographs - Awesome for talks
  
• FDA Approved indications clearly listed as well as likely palliative care uses
• Cost information (in actual dollars not some crappy $-$$$$ scale)
• Candid discussion about alternate route dosing/administration for many medications
• Detailed pharmacologic information in tables to compare different meds within a class
• A treatment monograph on 'Oxygen'  - When was the last time you read 4 detailed pages about the ins and outs of oxygen therapy? Wonderful!
• Monographs on related but not primary palliative care meds - A whole section on antifibrinolytic drugs! Bronchodilators! Diabetes meds! Potassium! Magnesium!  You get the point.
  
• Super helpful chapters covering meds in a meta-approach - Opioids and Fitness to Drive; Continuous Subcutaneous Infusions; Drugs Administered via Enteral Tubes
• Designed for use in the USA (as opposed to the UK version with UK only meds like diamorphine)

Here are the things I wish were included/changed/fixed:

• Better binding - it seems to be fragile after a lot of use, and my book gets used
• Not much info on fentanyl IV compared to transdermal and buccal routes
• The 2nd edition cover is a little boring compared to the Red, White and Poppy motif on the 1st edition.
  

If you are an AAHPM member you can get a 20% discount via the AAHPM website.  Also you could access it online via PalliativeDrugs.com but I find the book very useful and a rapid access to have at my desk.  And now with the extra copies I purchased it will be at almost all of my clinical sites.

Do you use HPCF-USA?  Tell me what you like best about it.

Disclaimer: No kickbacks given to any Pallimed author because of this post.  We did give away a HPCF-USA free edition back in 2007 for our winter contest.  And it was pretty cool when I met Robert Twycross in Austin and he recognized my name from Pallimed and told me he was a big fan of Pallimed.  But that is not why I wrote this.  Obviously I think this is a super awesome book.

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HemOnc Today has a personal essay from Dr. William Wood, an oncology fellow at UNC, about why he likes palliative care. He is in a cohort of medical learners with an increasing exposure to palliative care from medical school to fellowship. The historical perspective on the slow culture change in medicine to accept palliative care demonstrates an increasing acceptance with earlier and consistent access to palliative care teams. Here he describes working with the pallaitive care team during his residency:

"I was lucky to be in a program where my senior residents and attendings were heroes. Their thoroughness, competence and compassion were widely emulated by interns, who tried hard to live up to their examples."

Later in the essay, he makes an impressive statement referenced in the title of this post:

"As an oncology fellow, palliative care is everything it was before, but it has taken on a new dimension for me now — it is a refuge.

Paradoxically, though the goal is no longer cure or prolongation of life, providing this kind of care can feel extremely satisfying."

It is these satisfying interactions between professional and patient which inspire so many clinicians to pursue a career in palliative medicine or at least embrace palliative care from within their specialty. I am glad to see so many medical learners with the opportunity to have these personally rewarding opportunities to 'comfort always.'

He ends with a few probing questions about health care policy and the structure of oncology as a business:

"Yet, I am still troubled. Why does providing good palliative care feel like a refuge to me now in ways that it didn’t before? And why are there so many palliative care physicians who no longer primarily treat cancer? Could the structural and institutional organization of our cancer care delivery system, and the incentives therein, present subtle barriers to the ability of good oncologists to deliver good palliative care throughout the disease continuum?"

These organizational challenges to ethics may start to emerge in many specialties as we have more doctors like William Wood who promote palliative care within their specialties. When a critical mass of gastroenterologists start challenging automatic PEG placement without a exploration of the appropriateness and efficacy they may change policy or even reimbursement mechanisms. Same issue for oncologists and chemo, radiation oncologists and prolonged fractions when a few may do, or nephrologists and offering dialysis to patients they feel will not survive regardless of dialysis. We may be on the cusp of small internal revolutions in other specialties as palliative care education becomes the norm. What do you see at your institutions?

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Welcome to the inaugural edition of Palliative Care Grand Rounds, a monthly blog carnival bringing you the best and most interesting blog posts about hospice, palliative care, death and dying, grief, quality of life, communication in the medical arena, and anything else that strikes the fancy of the host that month.

If you are interested in becoming one of the upcoming hosts, please comment or email me at ctsinclair @t g-m-a-i-l d0t c0m. Here is the website with the archives and upcoming hosts.
If I ever get some spare time maybe we will get a creative little logo going.

Dethmama Chronicles is going to be the next host on Wednesday March 4th. (PCGR is a monthly blog carnival on the first Wednesday of each month.)

Don't feel you have to read all of these at once. Come back and nibble a little bit at a time. And if you read the posts from the other authors, leave a comment and let them know you want to see more!

FROM THE STAFF

Dr. Bob Wachter reviews the recent Archives of Internal Medicine paper showing patients have difficulty naming their doctors. He discusses many lessons learned from this study in his blog post. As you read it consider if palliative care teams suffer from the same problem. With all the members of your team it could be hard to remember who is who. But I imagine with increased face to face time discussing weighty matters it members of the palliative care team may be easier to recall. But currently that is just an untested hypothesis. Sean or Nate could you get on this?

Dethmama always enlightens and entertains with her recollections of interesting home visits as an on-call hospice nurse. The good ones this month are: "The Photo Op" with a surprise twist ending!, "A Talk with a Doc II", and "Hospice Hitwoman and the CYA."

A palliative care NP named Risa reflects on the bewilderment of family at how clinical inertia can overcome advance directives before anyone pauses to notice in her post "How Did This Happen?" She has another great post titled "Drifter" about how easy it can be to give someone a little respect when they were never given any.

Leo Levy at DNR/DNI completes the "My Code" saga. Great narrative style. Here is an example:

The code gets up to full speed. One of the nurses asks how many times we are going to do this. “Someone needs to bring the family!” I call out. This time my words find purchase. Eyes turn to the fellow. The rest of the team does not know about our conversation. Will she take this as a challenge to her authority? There is a moment of tension in the room. “It’s alright, go get the family,” she says

Hopeful LSW at Confessions of a Young Looking Social Worker posts the many reasons why she loves her job as a hospice social worker. Here are a few of my favorites from her post:

A man who helped build the Sears Tower (I was in awe of his courage)

A woman who was heavily involved in promoting a woman's right to vote and began several activist groups in her town...and continued to do her part after suffering a stroke at age 40...after the birth of her 6th son. Talk about strength!

A man who was a steeplejack, a trade he learned from his uncle that no longer exists

How do you want to die? In your sleep? Nibbled to death by the piranhas of senescence? Ask Duncan Cross.

HospiceNP lets us know the difference between "the work" and "the job."

Kevin MD brings attention to why it is so difficult to die in American hospitals.

Is being a hospice doctor depressing? Dr. David Tribble from the Alive Hospice Blog (welcome to the show Alive Hospice) lets you know it is not so depressing.

Dr. Bernstein from the Bioethics Discussion Blog asks which state is next for legalizing physician assisted suicide? What do you think?

Tigermom at Two Women Blogging posts a story about a friend with metastatic cancer who is also a therapist for others with severe illness. Does helping others cope, help you cope?

Aggravated DocSurg spins a story about the death of a trauma patient using the Four Horsemen as a unifying theme. Good literary stuff! Here is an excerpt:

Surgeons and anesthesiologists really don't like it when patients die in the OR, so after the "ex fix" has been placed and the femur appropriately splinted, Billy Bob takes his final ride tour of the hospital, to the ICU. Cold, coagulopathic, and comatose, there is nothing else that can be done, and Billy Bob continues to hemorrhage and eventually develops cardiac dysrhythmias and dies.

Good bedside manner is a key trait for the effective palliative care clinician. When your conversations sometimes go from zero to death in five minutes then you realize how empathy, compassion and good communication skills are wonderful assets to posess. Dr. Centor discusses the responsibility for attending physicians to model and teach good bedside manner. His blog post was spurred by a recent Pauline Chen article about the same issue in the NY Times.

FROM THOSE IN THE KNOW

There are so many interesting posts from Jessica Knapp at The Good Death that I could not just pick one. As a PhD candidate she is focusing on communication as a way to improve the way we approach death and dying. She covers mortuary bands, rights of same-sex partners in illness, and online grief support sites. But my favorite has to be "Cybertime" in which her mother opens a Gmail account and finds 177 unread emails from her recently deceased father. It is a MUST READ STORY!

Niko Karvounis at Health Beat Blog discusses the "Danger of For-Profit Hospices" in our future health care system with the awareness of the rapid expansion in the last decade and the increased scrutiny to the Medicare Hospice Benefit. ANOTHER MUST READ!

Les Morgan from Growthhouse has a great summary on funeral information and questions to ask. Would be great in pamphlet form!

Bill Colby, JD, known for his work in the Cruzan case and now a senior fellow at the Center for Practical Bioethics asks a very important question: Can Living Wills Work?

Tim Cousinais from the Palliative Care Success blog asks an important question and we need some answers: Will health reform accelerate or stall the progress of palliative medicine?

Wesley J. Smith has been a vocal opponent against euthanasia and physician-assisted suicide on his blog Secondhand Smoke. He recently posted a video called "The Euthanasia Blues." The only song I know with 'palliative care doctor' in the lyrics. For a good reflection of the chord this song strieks with people make sure to read some of the comments on his blog and on You Tube. Thaddeus Pope of Medical Futility writes about Smith:

"Smith often broadly attacks end-of-life mechanisms like PAS and unilateral withdrawal, even though such mechanisms can be invoked in justifiable circumstances. Nevertheless, he (and this video) are correct to imply that such mechanisms can be (and are) sometimes illicitly employed."

FROM THE PATIENT & FAMILY

Cancer patients have capitalized on the use of blogs to extend social support networks. The ability to update many with a few minutes at the keyboard seems so simple and yet the lives it impacts is so powerful. Anna Douglas, a popular BMJ blogger chronicling her experience with cancer died on February 1st. Her blog, From the Other Side, was started in April of 2008, and there are only a score of posts, but many offer great insights to her treatment.

HopefulLSW made note of another blogger with cancer, Kindra McLennan, who died on January 2nd of this year. Her post makes note of a Chicago Tribune story about the impact of Kindra's blog and some notable posts.

NPR's contribution to the cancer patient blogosphere has persisted despite the death of the initial blogger Larry Sievers. His wife offers reflections on her bereavement now that Larry is no longer with her. It is now expanding to a community titled, "Our Cancer." A recent post covered the occasional non-fit of a hospice nurse and a patient, but thankfully that experience did not make them turn their backs on hospice support forever. This would be the second time a hospice person would come into our home. The first time was a bad fit. We both couldn't wait for her to leave. So this time around, we were a little nervous.

Gail Rae from Mom & Me Journals relates the thin line caregivers walk when caring for a patient in decline when it comes to nutrition and hydration in her post "I Trust her with my Life." She compares her experience with a 1994 Law & Order episode entitled Golden Years, which focuses on formal and informal caregivers in conflict about feeding a frail home bound elderly woman.


Thanks for reading all the way to the end of the first edition of Palliative Care Grand Rounds. I hope you enjoyed some of the links. Any feedback about this new initiative would be great!!!

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Journal of Clinical Oncology has a double-blind, placebo-controlled trial of depot octreotide for the prevention of radiation-induced diarrhea. (The context here is that octreotide has some good trial data supporting its use to treat radiation-induced diarrhea.) This study involved 125 patients receiving radiation involving the entire pelvis (for a variety of malignancies); they received 20mg depot octreotide or placebo at enrollment and after 29 days. The study was powered at 85% to detect a 1-grade difference in diarrhea severity between groups.

It didn't look very good for octreotide. Diarrhea outcomes were essentially identical (incidence and severity) and the octreotide group had more adverse events (no biliary toxicity, but symptoms of GI cramping and constipation-like symptoms). Incidence of moderate to severe diarrhea was in the 20-30% range overall.

This study was done well enough that it's pretty safe to conclude that depot ocreotide is, indeed, worthless to prevent acute radiation associated diarrhea, and has signficant side effects. Given that there are some ok data for short-acting octreotide to treat diarrhea once it starts, I'm unsure whether this is an effect of depot octreotide itself or (more likely) simply a matter that the incidence of acute radiation induced diarrhea is low enough that prophylaxing for it with a drug with significant toxicities is just not worth it. Or both. Severe enteritis from radiation, while relatively rare, can be such a devastating and morbid complication (fecal incontinence, hospitalizations for hypovolemia, disruption in cancer therapy) that it's disappointing this didn't pan out....

J. A. Martenson, M. Y. Halyard, J. A. Sloan, G. M. Proulx, R. C. Miller, R. L. Deming, S. J. Dick, H. A. Johnson, T.H. P. Tai, A. W. Zhu, J. Keit, K. J. Stien, P. J. Atherton (2008). Phase III, Double-Blind Study of Depot Octreotide Versus Placebo in the Prevention of Acute Diarrhea in Patients Receiving Pelvic Radiation Therapy: Results of North Central Cancer Treatment Group N00CA Journal of Clinical Oncology, 26 (32), 5248-5253 DOI: 10.1200/JCO.2008.17.1546

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Methylnatrexone has hit the big time with a very timely publication of a industry funded double-blinded RCT in the New England Journal of Medicine. If you have been in palliative care for the past few years, methylnatrexone has been one of the drugs with some 'buzz' around it at conferences and in publications. We have touched on MNTX a few times here at Pallimed before.

This new study does not add much to previous knowledge about the medicine, but the study is the largest and most comprehensive one to date. Other double-blinded RCT's have already been published (JPSM 2008, Clin Pharm Ther 2000, J Pharmacol Exp Ther 2002, JAMA 2000) showing efficacy versus placebo without affecting analgesia from opioids. The patients were from nursing homes, hospices or palliative care centers and 60-70% were ECOG/WHO 3 or 4 (confined to bed more than 50%)

The participants were already on stable opioid doses, and stable laxative regimens with less then 3 reported BM's in the past week. More than 50% rated their 'constipation related distress' as moderate to severe. This seems to be a somewhat broad inclusion criteria. Constipation can be a very distressing symptom, but there are two types of distress from constipation: psychological distress of not 'being regular' and physical distress from GI discomfort. Many patients with advanced illness may have decreased number of stools for many reasons besides just opioid constipation, and I would propose that a regular number of stools for those with anorexia-cachexia syndrome and decreased functional status may be less then 3 per week. In assessing constipation related distress, managing expectations is part of good clinical care.

Interestingly less then 30% were on stool softeners, but most were on 2 laxatives of some category (stool softener, enema, bulk producer, contact laxative, or osmotic agent). I thought the percentage would be much higher in this population.

Of interest to some will be the oral morphine equivalent doses (OMED) these patients were on. I always find this interesting when seeing studies about hospice and palliative care patients, because opioids have a wide range of therapeutic dosing. The mean OMED was 339mg (+/-1214 )(placebo) and 417mg(+/-787)(MNTX) with a wide range in the study (9-10,160mg of morphine equivalents per day). For those readers who have not worked in palliative care you did read that number right. 10,160mg of morphine equivalents per day. If you ask anyone in palliative care they will probably tell you about the one or two patients they have seen up in that range. Now that would be a case-series to figure out how someone is tolerating those doses.

Sidebar:
As far as drug names go, I find 'Relistor' pretty uninspiring. Methylnaltrexone is fun to say, MNTX is easy to write, Relistor...eh. To me it sounds like a drug to get you back on a transplant list-> Re-listor=Re-lister. Or was Wyeth going for being 'realistic' about your constipation or advanced illness. Maybe they were trying to stay away from names that were too scatological or associated with OTC meds. Relistor just is uninspiring. (Sorry for the sidetrack, I find drug names fascinating.)

BTW the logo is pretty bland too. Come on now another circular logo? Are they trying to replicate the millions of hospice logos with 'embracing circles/hugs?' I would think something coming out of something else would be more representative. Any graphic designers or wordsmiths want to help Wyeth out?
(end sidebar)

I am sure many in palliative care are glad this medication is available and we will probably go through the next few months trying to figure out where it fits in the bowel toolbox. Thomas and the rest of the authors (and Progenics) should be commended for a well-designed research study in a hospice-oriented patient population. It would be a good article to review in a journal club to see how the study was designed and carried out, especially with so many institutions.

Overall the study is a good one, but it should be noted it was industry funded, which is notably very transparent in the article: "Progenics Pharmaceuticals designed the protocol and collected and analyzed the data." Is this part of the beginning of more pharmaceutical industry-palliative care/hospice collaborations? I would be interested to hear from Pallimed readers about their thoughts on the field's collaboration with industry. Is this a new source for funding and advancement of our field? Or is this a 'bogeyman' that is relatively absent from our small but growing field?

Of note there are two good editorials (here and here - sub required) in the issue regarding opioids and constipation.

(Disclaimer: I get nothing from Wyeth. Neither does Pallimed.)

(Advanced apology for the near-swear in the title for those who might be offended)

(Image from same issue of NEJM - not Opioid Induced Constipation)

(I like parentheses.)

Reference:

Thomas, J., Karver, S., Cooney, G.A., Chamberlin, B.H., Watt, C.K., Slatkin, N., Stambler, N., Kremer, A., Israel, R. (2008). Methylnaltrexone for Opioid-Induced Constipation in Advanced Illness. New England Journal of Medicine, 358(22), 2232-2343.

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1)
Lancet has a fantastic article about pediatric palliative care. It's both a general overview of the field as well as a lively discussion of the Big Issues in pediatric palliative care (pretty much all of which will be familiar to practitioners of adult palliative care). It has case discussions involving concurrent palliative & curative therapy, palliative care for terminal illnesses which go on for years, cultural issues, suffering, hope, international issues, etc. You can tell I really liked it. Also, some sanity about 'denial,' probably one of the most over-used labels we (medical people, not necessarily palliative care people) apply to our sick patients:

Adults aware of their impending death might maintain hope by shifting from a hope for cure to hope for what they define as a good death (eg, as pain free and comfortable as possible) and with a focus on leaving a legacy. How to support hope for children with life-threatening illness is less clear. An additional challenge is the struggle for parents and other loved ones to maintain hope. What remains unexamined is the role of “healthy denial” in maintaining hope for cure despite a very poor prognosis. It is possible that for some children and parents “unrealistic hope” in the face of overwhelming disease is a functional coping mechanism that does not necessarily signify pathological denial. At times, people might hold beliefs that although seemingly discordant with each other (eg, the knowledge that one is about to die at the same time as maintaining hope for a last-minute reprieve from death) could instead represent healthy coping.

The same issue also has a review of cirrhosis with some good general info on general prognosis (although nothing much beyond this Fast Fact), prognosis after transplantation, and up-&-coming therapies (?maybe) aimed at directly slowing/reversing liver fibrosis. Interesting stuff, but nothing about supportive care.

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Archives of Internal Medicine has a couple.

First is an attempt of sorts to validate an anticholinergic risk scale. The ARS was developed to try to quantify how likely a certain drug is to cause anticholinergic side effects (falls, dizziness, confusion, dry mouth, constipation, dry eyes, etc.). The scale gives a drug a 0-3 (none to severe) score for likelihood of causing anticholinergic side effects and then a patient is given a risk score which is the sum of their individual drugs risk sub-scores (2+3+3 = 8 - this would be for a patient on one moderate risk and 2 severe risk anticholinergic drugs). This study attempts to validate the ARS (which was developed relatively empirically based on pharmacologic know-how) in a geriatric population (geriatric clinic patients) by looking at risk scores with actual symptoms and comparing geriatric patients with general primary care clinic patients (on the assumption that older patients are more likely to suffer anticholinergic toxicities). Essentially they found that the AR scale & score were decently predictive of toxicities, particularly in the elderly, and they conclude that the ARS is a reasonable way of identifying high-risk patients. (There is a table with the risk scale as part of the article).

The other paper is about 'delicate' issues surrounding 'continuous deep sedation' (also variably known as terminal or palliative sedation) in the Netherlands. It is based on a survey (36% response rate) of Dutch physicians, and much of the context of the study involves the fact that these physicians have euthanasia as an option for them as well as terminal sedation. I'll only comment on a couple findings. First is that these physicians overwhelmingly differentiated between TS and euthanasia, apparently largely due to intentionality - their intention with providing deep sedation was to alleviate symptoms as opposed to bringing about death in euthanasia. The other point is that the use of TS exclusively for non-physical symptoms (i.e. existential suffering) was relatively rare (~8% overall - rates are much higher than this for euthanasia). My overall gloss on this (and this is not the first bit of research out of the Netherlands to suggest this) is that - even in a setting where both practices are available - TS and euthanasia are conceived of differently by practitioners, and used differently for different situations/patients.

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Coincidentally, BMJ has a paper (again a survey) describing the epidemiology of the use of CDS in the Netherlands: how often, what reasons, use of artificial fluids/food, etc. Most physicians (again, this is all based on physician retrospective reporting) felt that it either didn't shorten life or did so on the order of less than a week. The one interesting bit here, and perhaps one that contradicts my earlier pontificating, is that rates of euthanasia are declining in the Netherlands whereas the percentage of people who die while receiving CDS is increasing which makes one wonder if one is being substituted for another...?

The accompanying editorial's subtitle is also worth mentioning: "Imprecise taxonomy makes interpreting trends difficult" and discusses the ongoing struggle involving language (TS vs PS vs CDS, etc.).

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Mayo Clinic Proceedings has two reviews. One is a discussion of informed consent - quite legalistic but a good basic review of the topic, its history, etc. The last section discusses autonomy and how patients actually want decisions made and I enjoyed this line: "Responsibility for medical care has landed on the shoulders of patients with a resounding thud."

The second is a review of small cell lung cancer. Picking up our on & off again habit of noting whether supportive care is mentioned in review articles of nasty, nearly uniformly terminal illnesses I'll point out that, in fact, there was no mention of anything like that.

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JCO has a really compelling reflective piece on death & blame. It starts off about patients/families blaming someone (oncologists, etc.) for the fact that treatment often doesn't work and then goes into a discussion about the place of death in our culture - is death fundamentally a wrong (in a deep moral and spiritual sense) or not? The problem is of course one can deeply believe that death is not wrong but that doesn't mean that 1) your patients agree, and 2) it doesn't deeply suck (hurts on the inside & the outside so to speak) anyway (to quote Christian quoting me - see the last post).

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Age & Aging has a study about a prognostic index for determining 4-year mortality for the elderly. It's based on prospectively gathered data on ~1000 patients from a single region in Italy and uses relatively easily obtainable data (could be obtained from a single office visit). Patients in the highest risk group had a 78% 4-year mortality - although it needs to be noted that only a very few patients fit into this group and so it becomes very difficult to interpret its validity. Indices like this are helpful in two ways: 1) as a research tool (risk stratifying subjects, etc.), and 2) to identify patients with more urgent indications for advance care planning, etc. What's unclear is if they offer anything further (clinically) than reinforcing the maxim that 'sick people are sick.' Thanks to Dr. Bob Arnold for alerting us to this.

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Finally, and don't call me crazy for noting this, JAMA has a primer about interpreting large genomic studies. It's likely that at least my generation will be faced with actually clinically useful genomic studies (about predicting efficacy/toxicities of opioids and other meds at the very least) and knowing what to make of these studies will be an important skill.

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A rather academic post: genetics and some prognostically relevant papers.

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Cancer has a study on genetic variations and response to morphine in cancer patients. The data comes from a prospective study of ~220 advanced cancer patients who were receiving morphine for pain. They were treated per a palliative care team's protocol and about 60 of them were rotated off morphine due to inadequate analgesia +/- intolerable side effects. This analysis compares rates of certain genetic polymorphisms between patients who 'did well' with morphine with those required rotation (it is unclear from this paper if the clinicians treating these patients were blinded to the genetic analysis or even when those analyses were done in relation to the patients rotating off morphine). They were looking at certain (known) variations in the multidrug resistance (MDR-1; it is implicated in penetration of drugs across the blood brain barrier amongst many other things) and catechol-O-methyltransferase (COMT; involved with monamine metabolism and implicated in pain modulation) genes.

Responders and switchers were were matched demographically at baseline. Before we get to the genetics the differences and similarities between the groups are worth noting. Obviously switchers reported less pain relief and more side effects and particularly drowsiness, confusion, and hallucinations were associated with switching in regression analysis. Morphine doses however were similar between groups however morphine serum levels were lower in the switchers. There were no correlations between morphine dose, analgesic response, or morphine/morphine metabolite serum levels. All of this reinforces the long-held observation that analgesia (or for that matter dose limiting side effects) don't per se have much to do with morphine dose, serum levels, etc. (The one exception here is that myoclonus was associated with total morphine level).

I'll be the first to admit here that I am not qualified to judge the genetic analysis segment of the article (please comment though if you've read the article and have the requisite background to comment intelligently on it). I think it's safe to say the results are intriguing and hypothesis generating. Essentially they found that certain COMT polymorphisms were associated with the need to switch; MDR-1 variations weren't; however certain MDR-1 variations (as well as COMT ones) were strongly associated with CNS toxicities like drowsiness, confusion, and hallucinations. A few things to note here: all switchers were changed to oxycodone and they (off-handedly) mention that most of these patients did well with the switch (suggesting that this is a morphine and not an opioid-class effect; which is not to say that oxycodone is 'better').

The astonishing individual variation in response to opioids is a fascinating thing and a clinical challenge, and maybe one day we will be able to rationalize it. One patient can be crippled (literally) by painful bone mets and fractures and have their pain well controlled with 25mcg/hr of transdermal fentanyl with a few doses of 15mg of morphine for breakthrough; the next patient with a similar clinical picture is on 5mg/hr of intravenous hydromorphone. I had a patient once who was on ~2 grams a day of oral oxycodone (with pretty good analgesia); the moment he got into the hospital and got a whiff of intravenous hydromorphone he would be delirious (and didn't get much pain relief). I am hopeful that in the next couple decades why this happens will be much clearer, and research like this (and this) will help clarify things further; it seems that pretty soon all our patients will be getting shot-gun genomic analyses anyway and maybe this will provide our profession some useful information regarding drug selection and toxicity.

Ross, J.R., Riley, J., Taegetmeyer, A.B., Sato, H., Gretton, S., du Bois, R.M., Welsh, K.I. (2008). Genetic variation and response to morphine in cancer patients. Cancer DOI: 10.1002/cncr.23292

[Cancer also has a study on symptom burden after autologous stem-cell transplants for myeloma: things get bad really fast, then get better, and pre-existing symptom burden was the best predictor of symptom burden 30 days post transplant.]

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Lancet Oncology has a study relevant to prognosis in pancreatic cancer. It looks at the prognostic utility of CA 19-9 response in patients with advanced pancreatic cancer (did those whose 19-9's dropped dramatically do better than those whose didn't). The data come from a prospective chemotherapy trial involving ~350 patients (~250 of whom had CA 19-9 elevations at baseline). Median overall survival was 7.7 months and which was similar between those with baseline normal and baseline elevated 19-9's. 19-9 drop, neither velocity nor magnitude, was not associated with improved survival. However, those patients whose 19-9's were above the median 19-9 level of those with elevated 19-9's had significantly worse survival (6 month 50% survival vs. ~11 months). Let me clarify that sentence: looking only at those with elevated CA 19-9's, the median elevation was 59 times the upper limit of normal (~2000U/mL); those patients whose 19-9's were higher than that median elevation had a worse prognosis (despite, intriguingly, having a similar response to chemotherapy). This was a large trial with prospectively gathered data and it is good supporting evidence that very high CA 19-9 elevations predict worse survival (average ~6 months) in pancreatic cancer.

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Mayo Clinic Proceedings has a small study about a single center's (the Jacksonville Mayo) experience with liver transplantation (its focus is on what happens to those patients who the transplant committee declines to list). It mentions the outcomes of those who were initially listed including the number who die while listed: 5% (the mean time to transplant was 46 days which seems really short to me). Frustratingly it doesn't mention what happened to the patients who were denied transplants due to significant comorbid medical illness.

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BMJ has an article relevant for long-term prognosis in stroke. It is based on data from 3 large cohort studies on the natural history of ischemic stroke in patients in the UK (involving over 7000 people; overall survival at 6 months was ~75%). This study looks at those patients who were alive at 6 months and sees if their functional status at that point predicts prognosis. Not surprisingly, it does: the most disabled patients who made it 6 months had a median survival of 2.5 years; those patients who weren't functionally dependent had a median survival about 6 years; functionally independent patients lived ~10 years. (They used Rankin Scores to define disability).

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There are two more articles from December's Journal of Pain & Symptom Management that I wanted to highlight.

First, there's a brief piece about using propofol as an anti-emetic and sedative in palliative care. It's essentially a case series of 35 patients in a palliative care unit who received propofol over 10 years in Stockholm. I'm not going to make much of its use in palliative sedation--it seems to work, the authors show their dosing data, it's probably no more or less dangerous that palliative sedation with benzodiazepines or barbituates. What is more interesting is their use of it to treat refractory nausea/vomiting. They present experience from 13 patients whose nausea persisted despite most typical antiemetics being thrown at them. In only 3/13 was treatement limited by excessive sedation, and most of the rest had good control of nausea with propofol without dose-limiting sedation. Doses were generally less than 1mg/kg/hour, and the authors recommended starting at 0.5mg/kg/hour and titrating to effect. (Be warned: data was not collected prospectively or in an organized/standardized fashion for this case series--my overall take on this data is that it's proof of principle for propofol as an antiemetic but not much more).

Second, long acting octreotide is examined for malignant bowel obstruction for ovarian cancer. The findings aren't promising, but this study is so small and preliminary that really no conclusions can be drawn. This was a pilot trial on 13 people with advanced ovarian cancer and bowel obstruction (however, 5 of them didn't evidence of bowel obstruction when imaged!) who were ineligible for surgery. They received the "depo" form of octreotide. Results were a complete wash--over half had no evidence of response. 3 patients did remain on it for more than 8 months leading the authors to remark about its "safety and tolerability," which is swell, but "efficacy" is important also. The study is so small, and the patient population probably poorly chosen, that by no means can long acting octreotide be written off, although its use currently can't be endorsed outside of a trial either, especially when there's at least some decent, positive data for short acting octreotide.