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by Ross Albert

Every so often, you come upon a study that validates your clinical practice and approach. This was my feeling when I read the research letter “States Worse Than Death Among Hospitalized Patients With Serious Illness.” This study out of Philadelphia surveyed 180 hospitalized patients with serious illness on their views of various health states, and how severe or unacceptable they considered them. What was fascinating was that the scale used was based on death as the benchmark on their Likert scale—“worse than death, neither better nor worse than death, a little better than death, somewhat better than death, or much better than death.”

The study revealed that in this group of patients with advanced cancers, heart failure, and COPD, health states with significant dependence on machines and on care from other people were frequently deemed “Worse than death.” Greater than 60% of respondents rated bowel and bladder incontinence, bedbound state, and ventilator dependence equal to, or worse than death. For comparison, their findings showed that wheelchair bound state, constant moderate pain, and being home bound were deemed equal to, or worse than death less than 15% of the time.

How can we incorporate this study into our practice? The study and author discussion remind us that discussing goals of care in the context of simply being alive or not is insufficient. When providers continue treatments that at best would lead to a state of living that patients and families would find worse than dying, they are not practicing person-centered care. As any card-carrying palliative care provider would note, goals of care discussions must continue to focus on patient’s values and preferences, hopes and worries. This study helps to validate our approach, and continues to build the literature base in our increasingly evidence-based field.

Reference:
Rubin EB, Buehler AE, Halpern, SD. States Worse Than Death Among Hospitalized Patients With Serious Illness. JAMA Internal Medicine. Published online August 1, 2016.

Dr Albert is the chief of the division of palliative medicine at Hartford Hospital, and the medical director for the Hartford HealthCare at Home Hospice teams, in Hartford CT.

Photo Credit: "handle with care fragile do not drop" by Jenny Johnson via Flickr CC-AT-NC

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by Dr. Katherine Sleeman

On Tuesday 17th March from 3-4pm UK time (9-10am Central Standard Time) we will be holding the monthly Twitter Journal Club for hospice and palliative medicine: #hpmjc. The aim of the journal club is to provide an informal multidisciplinary forum for discussion of research findings, and we hope you will join us.

You can find some more information about the #hpmjc journal club here.

The paper for discussion this month is ‘High-flow oxygen and bilevel positive airway pressure for persistent dyspnea in patients with advanced cancer: a phase II randomized trial’. The paper was published in October 2013 in The Journal of Pain and Symptom Management, and is open access .

Lead author of the paper, Dr David Hui (@DrDavidHui) will lead this month’s journal club, and will be available to answer your questions on his study. Dr Hui is an assistant professor at the Department of Palliative Care & Rehabilitation Medicine and the Department of General Oncology, The University of Texas MD Anderson Cancer Center. His research interests include symptom management clinical trials, research methodology, prognostication, and integration of supportive/palliative care into oncology.

Background?

Breathlessness is one of the most distressing symptoms in cancer patients. Many patients continue to experience refractory breathlessness despite treatment with opioids, steroids and low flow supplemental oxygen. Novel strategies are needed to address this symptom.
This paper reports a randomised crossover trial of high flow oxygen and non-invasive ventilation. High flow oxygen is a novel gas delivery device that can deliver up to 40 L/min of humidified oxygen via nasal cannula. Bilevel positive airway pressure (BiPAP) provides not only oxygenation but also ventilation and thus respiratory muscle support.

What did the study find?

Among the 30 patients randomized, 13 completed 2 hours of HFO and 10 patients completed 2 hours of BiPAP. The total completion rate was 77%. In a before and after comparison, patients reported improvement in their breathlessness with high flow oxygen (mean change in numeric rating scale 1.9; P=0.02; mean change in modified Borg scale 2.1, P=0.007) and with BiPAP (mean change in numeric rating scale 3.2; P=0.004; mean change in modified Borg scale 1.5, P=0.13). Some physiologic parameters improved. No significant adverse effects were observed.

Questions for discussion:

• Do you have experience using high flow oxygen?
• What do you think about the study findings?
• What are the mechanisms in terms of how high flow oxygen and BiPAP relieve breathlessness?
• Is it ethical to provide non-invasive ventilation in the palliative care setting?
• What are some advantages and disadvantages of crossover designs?
• What are the implications of this research for your practice?

We look forward to discussing this on 17th March, and hope that you can join us. Just follow @hpmjc and use #hpmjc

Archive of past #hpmjc can be found here.

Katherine Sleeman is a clinician and academic in palliative medicine, Cicely Saunders Institute, King’s College London.

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As David Currow said when he received his Excellence in Research award, hospice and palliative medicine researchers need to meticulously measure toxicity in addition to benefits of palliative interventions. How do you think the State of the Science studies did with this goal? What do you think about the conclusions of each of the studies? Any changes in your practice? Thanks to the presenters Jay Horton, Kimberly Johnson,Nick Dionne-Odom, and Cardinale Smith for reviewing and presenting. Always a fun presentation.

Neurolytic sympathectomy in management of cancer pain-time effect: a prospective, randomized multicenter study http://t.co/fdqI1A2meB #hpm15

— Lyle Fettig (@lfettig) February 28, 2015

Comparative effectiveness-senna to prevent problematic constipation in peds onc patients receiving opioids:http://t.co/rYyx3xY7jI #hpm15

— Lyle Fettig (@lfettig) February 28, 2015

Randomized Controlled Trial of Expressive Writing for Patients With Renal Cell Carcinoma http://t.co/2reY7q5CM0 #hpm15

— Lyle Fettig (@lfettig) February 28, 2015

Safety of benzodiazepines and opioids in very severe respiratory disease: national prospective study http://t.co/CsbkLEa0jF #hpm15

— Lyle Fettig (@lfettig) February 28, 2015

An integrated palliative and respiratory care service for patients with advanced disease: An RCT http://t.co/awhOMOKRAy #hpm15

— Lyle Fettig (@lfettig) February 28, 2015

Inpatient palliative care for patients with acute heart failure: outcomes from a randomized trial. http://t.co/HCRVaXRIw4 #hpm15

— Lyle Fettig (@lfettig) February 28, 2015

Intervention to improve care at life's end in inpatient settings: the BEACON trial. http://t.co/Ht7MwhzIYF #hpm15

— Lyle Fettig (@lfettig) February 28, 2015

Association of experience with illness and end-of-life care with advance care planning in older adults http://t.co/S04ifi57iM #hpm15

— Lyle Fettig (@lfettig) February 28, 2015

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By Katherine Sleeman

On Thursday 26th February from 9-10pm UK time (4pm New York, 8am 27th Sydney) we will be holding the monthly Twitter Journal Club for hospice and palliative medicine: #hpmjc. The aim of the journal club is to provide an informal multidisciplinary forum for discussion of latest research findings, and we hope you will join us. You can find some more information about the journal club here.

The paper for discussion this month is 'An integrated palliative and respiratory care service for patients with advanced disease and refractory breathlessness: a randomised controlled trial’. The paper was published in December 2014 in The Lancet Respiratory Medicine, and is open access.
This month’s journal club will be led by Katherine Sleeman (@kesleeman), Clinical Lecturer at the Cicely Saunders Institute.

Why this paper?

Breathlessness is a common and distressing symptom in advanced diseases such as lung cancer, chronic obstructive pulmonary disease (COPD) and heart failure, and is often difficult to manage.

This paper reports the results of a randomised controlled trial of an early integrated breathlessness support service for patients with refractory breathlessness (breathlessness that persists once treatment of the underlying disease is optimised). The breathlessness support service was a multi-professional integrated service combining respiratory, physiotherapy, occupational therapy, and palliative care.

What did they find?

105 patients were randomly assigned over 2 years to receive either the breathlessness support service or usual care. The primary outcome was breathlessness mastery at 6 weeks after randomisation. The authors found that breathlessness mastery improved in the intervention group compared with the control group. Intriguingly, they also found that survival at 6 months was better in the breathlessness support service group than the control group.

Questions for discussion:

In your experience, is unrelieved breathlessness is a significant clinical problem?

What are the advantages of a fast track trial in palliative care?

What do you think of the primary endpoint of ‘breathlessness mastery’?

Are you surprised by the improved survival in the intervention arm? What might be the mechanism?

Are randomised controlled trials of palliative care that have patient survival as the primary endpoint needed?

We look forward to discussing this on 26 February, and hope that you can join us. Just follow @hpmjc and use #hpmJC on Twitter.

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The physical exam is an important skill for the practitioner of palliative medical arts because we may be working with patients in their home where technical diagnostic options are limited or in a treatment mode that has been defined by avoiding further diagnostic tests.  So I am particularly interested by any article that discusses clinical examination skills relevant to palliative medicine.  Of course the title did not hurt in causing me to pause.  "Gurgling Breath Sounds May Predict Hospital Acquired Pneumonia" by Dr. Rodrigo Vasquez et al. published in Chest (article behind paywall) is one of only 6 articles in all of PubMed that have 'gurgling' in the title.

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A growing number of studies have focused on the psychological burden of advanced disease.  A recently published study in Critical Care Medicine evaluated the psychological burden in patients with COPD and their caregivers after an ICU stay.  The study was performed in France by the same group that brought us the trial of an ICU communication intervention published in NEJM a few years ago.

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Drawing of a nasal cannula from Wikimedia Commons

It's a common assumption amongst both the general population as well as medical professionals that breathlessness equals some problem with oxygen delivery, and therefore, every patient with dyspnea should have at least a little bit of oxygen delivered through a nasal cannula regardless of their oxygen saturation (sometimes endlessly).  Because of the ubiquitous nature of oxygen therapy, why not?  It helps many patients, and it makes sense that the higher concentration of O2 molecules represents the critical component of the therapy.  It's been shown to palliate dyspnea, improve functional status, and prolong life in patients with COPD with hypoxemia. 
Hypoxia isn't always the cause of dyspnea, however, and Abernethy et al. set out to test the hypothesis that room air delivered by a concentrator at 2 liters per minute might rival the efficacy of oxygen delivered at the same rate for patients with advanced disease, refractory dyspnea, and normal blood oxygen concentrations (Pa02 >55 mmHg).  The results of the double-blind, randomized control trial were published in Lancet recently. 

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We have featured blogs here from social workers, doctors and nurses in the hospice and palliative medicine field, but we have never featured a blog written from a hospice patient.  Judi Chamberlin has been writing "Life as a Hospice Patient" and just had her one-year blogging anniversary December 4th.  She has led a very active life including being an activist in the psychiatric survivor movement since 1971 and author of "On Our Own," (available from the National Empowerment Center (http://power2u.org/). One of her goals is to ensure that people labeled as "mentally ill" have the same rights as others and to prevent their marginalization and discrimination.  Her activist background has been continued with her blog about her hospice experience.

Her hospice story was even featured in the Boston Globe because her insurance had reached it's lifetime $5,000 hospice benefit limit.*



Some highlights from Judi's posts:

From the post "An even stranger day":

Meanwhile, I was attempting to manage my symptoms of feeling generally awful, and I used enough morphine, ativan, and ABHR gel to finally start feeling better, with no more pain, and just a slight amount of spaciness, which seemed like a reasonable trade off. Combined with the general pattern of feeling better as it gets later, I'm feeling better right now than I have all weekend. Yesterday I needed resting chairs to get from bed to the living room, but today I made it without the chairs, and I've gone back and forth to the bathroom as well without getting totally exhausted (a big change from yesterday).

From the post "...and more sleep...":

Marty, Marie, and I had a good conversation on Tuesday, in which I expressed my fear of hitting a plateau in this extremely weak state and just lingering here. This is the worst thing I can imagine, growing more and more miserable and frustrated as I can do less and less. And today we met with Nancy, and I talked about the same fears. I am just so weak and feeling so blue. Even doing simple things, like writing out some checks, feels like too much. I just want to lie here and watch TV or read the paper or do crossword puzzles.

I keep drifting off into a state of semi-sleep where I can hear the TV or the conversation in the room and think I am participating but of course am not making any sense. I'm tired and bored and frustrated and just don't want to go on like this much longer. 

From the post "Hospice--patient centered care":

The hospice movement attracts certain kinds of people, who find it rewarding to work with dying patients, although I suppose many people would not find it appealing work. But in all my experiences with hospice, both when my dad was a hospice patient, and now my own, I have found a group of people who are upbeat without any kind of false cheerfulness, but who instead can help to find a positive aspect in any situation.

When I first came into hospice, I was shown a diagram of patient-centered care, with the patient represented by a big circle in the middle, surrounded by smaller circles standing for family, nurses, social workers, etc., all of whom are there to help the patient achieve his or her goals. So when I said I wanted to go to Omaha, many people at both agencies had to do a lot of things to make it possible, without any sense that they were going out of their way or doing something "extra" or unnecessary--if it was something I wanted to do, hospice was there to make sure it happened.

She writes very openly allowing us to see her raw feelings and honest reactions to the people around her.  Go read through Judi's blog and leave a comment and let her know someone is listening.

*That's a story for another day.

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This will be the last of the Mag Citrate posts for now. And after reading this monster you'll thank me. That said, these are all notable papers, each which I hope will be of interest to at least some of our readers: the progno-wonks, the teaching-filists, the EBM-purists, and the Terrible Things We Do To Our Patients-people.

(Images chosen because they are pretty and available under a CC license. See here for an explanation of the photographic technique used.)

1)
Cancer has a paper about prognosis in advanced biliary cancers. The data come from ~200 patients with unresectable biliary cancers (gallbladder, intra & extrahepatic cholangiocarcinoma) who were enrolled in a variety of studies earlier this decade (it's a Korean study group; unclear if all the patients were Korean). Data were collected both prospectively and retrospectively. All of the studies involved chemotherapy (ie these were patients 'well enough' to be enrolled in chemotherapy studies, which means that if anything these findings overestimate survival). Mean age was 59 years; most patients had metastatic disease and a quarter of included patients had recurrent/metastatic disease (meaning they initially underwent resection, and 'enrolled' in this study at the time recurrence/metastasis was diagnosed).

Gross survival data were presented: median survial was 7 months, 6-month survial 57%, 1-year survial was 28%, 2-year ~10%, and 3-year and beyond was less than 5%. They did a multivariate regression analysis, and in the end having intrahepatic cholangiocarcinoma (vs the other biliary tract cancers), liver metastases, poor performance status, and metastatic disease (vs. locally advanced) were all associated with worse survival. The authors tied this up into a prognostic index to stratify 'better' and 'worse' prognostic groups. Frankly, though, it's all dismal, and without further investigation of this prognostic index, these gross survival data are the most helpful.

2)
Thorax has a review on the role of opioids for dyspnea in COPD. It's a narrative review, which gives some history, reviews the literature, and discusses barriers to opioid use for dyspnea. One major point they make is that despite the consistent research findings that opioids are effective for dyspnea in COPD, long-term use has not been studied at all (most trials involved single doses or were for less than a week). The authors discuss their approach to using opioids for dyspnea - one could describe it as starting extremely low (e.g. 1-2.5 mg of oral morphine) and going extremely slowly; quite a different approach than how most of us use morphine for pain.

They also outline a wide-ranging research agenda. In it they do mention the issue of patients with pre-existing hypercapnea (CO2 retention). I hope someone addresses this, as it remains an important question at least in my practice. The aforementioned research, all of which supported opioids' safety/efficacy (including that they don't seem to induce hypercapnea), was all done in patients without chronic hypercapnea, and I think it remains a real question if opioids are safe in this population (assuming patients have a longer prognosis and goals which aren't strictly symptom-alleviation). (See here for a good systematic review of the research ([it misses a few recent studies, none of which however answer the above questions]). If you've got a patient with a baseline pCO2 of 60, an indeterminate prognosis, chronic and distressing dyspnea which hasn't responded to other interventions - do you give them opioids?

3)
On the 'real evidence' front, NEJM has a sobering analysis of selective reporting of outcomes regarding the use of gabapentin for off-label purposes (most of these were investigating gabapentin's use for chronic and neuropathic pain). They note that much of the information in this analysis comes from documents which were made available as part of an investigation into the manufacturers' off-label marketing of the drug. Internal research protocols were evaluated, and, among other things, compared to what was actually published/made public from the studies. They found that over half of the publications of these trials (8 of 12 published trials) either published secondary trial outcomes as primary outcomes (ie in the research protocol an outcome was designated as a secondary one, but published as if it was the primary outcome) or published secondary outcomes in a manner indistinguishable from the protocol designated primary outcome, or published novel secondary outcomes (ones that weren't ever specified in the research protocol). They also demonstrate that, not surprisingly, for most of these publications which fudged the primary outcome it made gabapentin appear more effective.

Their bottom line: We are concerned that the reporting practices observed in our analysis do not meet the ethical standards for clinical research or maintain the integrity of scientific knowledge. Fair and honest treatment of patients enrolled in clinical trials of any kind requires full, open, and unbiased reporting. Journal publication, a formalized platform for scientific discourse and dissemination of knowledge, should not be used as a marketing tool for off-label drug use.

It's impossible to know how widespread these practices are, and they point out that all this comes from the fact that gabapentin's manufacturers were investigated for inappropriate off-label marketing of the drug (ie we have reason to believe already the manufacturers weren't playing by the book). Nonetheless it's a real warning that the grain-of-salt that we all take with purely industry funded research is not just paranoia or nit-picking skepticism. Of real importance is the reality that there remains a good amount of either unpublished or 'grey' published research - and that what we see tends to be the Drug X Works publications, particularly if research into the drug is industry-only supported. I think gabapentin works, probably most of us who read this think so, albeit modestly so - but what we know about how well it works is probably overstated, however.

4)
JAMA recently published a report looking at broad demographic trends in hip fractures in older patients (over 65 years), which has some prognostic data (we visited this topic a couple years back: see here, item 3). Huge study, using 20 years' worth of Medicare claims data. The gross survival data were in the ball park of the study I just linked to: 1 year survival was ~22% for women, 32% for men. So not quite the sentinel event for older patients with advanced dementia (see here), but not great either.

5)
Archives of Internal Medicine recently published a brief report of a survey of physicians' experience with and satisfaction with chaplains. The data come from a large national survey of physicians (N=1100, all specialties and practice types, about a 62% response rate). Basically most physicians had worked with chaplains and were satisfied with the work chaplains did. A couple things I found interesting about this. First was its use of 'R/S' throughout to denote 'religion/spirituality.' Something about this bugged me, which is weird since I'm generally pro-acronym and not too sensitive about religion/spirituality. Second was this snap-shot of physician belief :

Of the respondents, 10% reported no religious affiliation, 59% reported being Christian, 16% reported being Jewish, and 14% reported other affiliations; 41% agreed with the statement, "My whole approach to life is based on my religion." Forty-one percent of the physicians believed it was appropriate for them to talk about their own R/S with patients when the patient asked about it. Fifty percent of the physicians believed it was appropriate for them to pray with patients when the patient requested it. The physicians reported that R/S "often" had a positive impact on their patients...and "rarely" had a negative impact....

6)
I think I was so distracted by the vertebroplasty debacle in August that I forgot to mention another paper from the same article in the NEJM on prognosis after cardiac arrest. This is excellent teaching file material, particularly for fellows - while these guidelines remain the most widely used ones, this paper has a couple important additions to those. First, and speaking personally here, it has a welcome explanation of the whole somatosensory evoked potentials/N20 response test (an EEG/electrophysiologic test). This is something I've read about, seen my neurology colleagues employ it, but not really have any idea what it involved: this paper explains it (although does not speculate as to why an absent N20 response is such a dire prognostic indicator). Second, it discusses hypothermia protocols and what they might do to prognosis. No answers here, although there's reason to think that hypothermia may improve the general prognosis for those with anoxic ischemic encephalopathy and no brisk/early signs of recovery from absolutely wretched, to just very poor. The author did note that in a recent trial a few patients who had no-better-than-extensor motor responses on day 3 (which has been considered a near universal marker of near zero chance of meaningful recovery) improved by day 6 (showed signs of awareness). Given that many families decide to cease life-prolonging measures several days out from an arrest it's unclear how best to study this: including only those who live a while and whose families choose to continue life-prolonging treatments will overestimate survival and neurologic recovery, as inevitably these patients will be younger with fewer comorbidities than those who died after discontinuing life-sustaining treatments....

7)
The American Journal of Speech-Language Pathology has a paper about SLP's attitudes and beliefs about feeding tubes for patients with advanced dementia. It comes from a survey of a national sample of SLPs (n=350, 57% response rate). The data are confusing, at least on one level. About 80% believe FT improved the nutritional status of patients with advanced dementia and eating problems; about half thought they improved functional status; only 40% thought they improved quality of life. About 40% thought they were the standard of care in their community, although 15% thought that should be the case. About 56% of SLP, given a case of a patient with advanced dementia and dysphagia, said they'd recommend a PEG tube placement.

However, when given a similar scenario, only 11% said they'd want their family to ask for a PEG tube to be placed in them.

This is a stark demonstration of the chasm between what most of us would want for ourselves if we developed advanced dementia (be comfortable, no tubes) and then what we (health professionals) actually do to our patients (for, yes, extraordinarily complex reasons, which includes struggling family members).

I'm beginning to keep my eye out for research about the differences between what people want to happen and what actually happens. Let me rephrase that since most of us want to live long and healthy lives and die relatively quickly after a brief illness. So defining that chasm is an easy one. What I mean is research which more directly looks at what agents in our health care system (whether clinicians, family members, or patients) say they want/they'd want for themselves, then end up getting/doing. One example - which I think is a real study that I didn't hallucinate but can't for the life of me find now (please comment if you know this study) - looks at proxy decision makers for patients on chronic ventilators (chronically critically ill patients - I don't think these were quadraplegics or patients with ALS), asking them why they chose to keep their loved one on a vent, whether they regret it, etc. This study also asked the proxy (family member) if something similar happened to them would they want their family to maintain them on a vent like this. Most said 'No' - although they were electing to do this same thing to someone they loved. It really struck me as emblematic for so much of what we see go wrong here, and underscores a theme that I've returned to on the blog multiple times - is this a 'problem' with families? with individual clinicians (if we just counseled people better, gave clearer/more coherent/stronger recommendations/owned these decisions more - a lot of this could be avoided)? or with The System?

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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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Imagine a nurse in the ICU raises concerns about possible euthanasia by staff in the ICU. You might think it may first go to the ethics committee, the hospital board, and likely the legal department. Then imagine if the Feds (Office of Inspector General) get involved and conduct a complete investigation into the allegations of hastened death. Really. Just imagine it happening to you.

Makes answering, "Hey honey, how was your day?" seem impossible.

Now imagine someone in your department says, "You know what we should do? We should publish our experience of being investigated by the OIG in a major medical journal!" Would you not want to throw a drink in that guy's face?

Well thank goodness someone did think that was a good idea, because Chest published an important article regarding ICU & Palliative Care ethics this month from the group at VA Palo Alto. They are to be highly commended for shedding some light on this very difficult subject.

The paper discusses four cases of alleged euthanasia in detail as well as the investigation and the changes made by the ICU staff to improve communication and standardization of comfort care orders.

Briefly here are the four cases (there are many more details in the original article):

Man in his late 50's with metastatic lung cancer to the brain, with hemorrhage into his brain, and respiratory failure requiring a ventilator. Family and clinicians agreed to comfort care as the primary goal and the vent was discontinued and the ET tube left in place. Over two days, he received increasing doses of morphine eventually getting 30mg/hr. Another nurse felt this to be excessive and she titrated down to under 10mg/hr. He was extubated 3 days after the vent was stopped and died that morning.

Patient in his mid 60's with metastatic lung cancer on a ventilator with pneumonia and ARDS. Goals were changed to comfort care. Vasopressors were stopped and 100% oxygen per vent was decreased to 21%. He was continued on fentanyl (1oomcg/hr) and midazolam (2mg/hr) without titration. He died minutes later.

Another man in his mid-60's with metastatic lung cancer with pneumonia and sepsis, renal failure and eventually requiring a ventilator. After 1 week goals were changed to comfort care. His oxygen concentration on the vent was decreased from 100% to 21% and vasopressors were stopped. The ventilator, fentanyl and midazolam were all continued and he died two hours later.

Man in his mid-50's with metastatic colon cancer with neutropenia, respiratory failure and sepsis. Placed on a ventilator, vasopressors and antibiotics. He required paralyzation and sedation (fentanyl 200mcg/hr & versed 6mg/hr). After 36 hours family requested comfort care, the paralytic, pressors, and ventilation were stopped. No titration of the fentanyl and versed. He died within minutes.

Of particular note the last three deaths happened on the same day, which brings to mind the impact of death acuity. So many deaths in such a short time can be very shocking to staff and in other situations unusual grouping of deaths in medical settings has been a tip off for identifying health care professionals who are killing patients.

Another significant issue was the concern that the deaths were hastened to possibly open up ICU beds for other patients. This allegation was not supported by the OIG's investigation.

The results of the OIG inspection are online and basically found no substantial evidence for intentionally hastened death but did find there was significant variations with the interpretation of appropriate end of life management in the ICU, and recommended the establishment of new guidelines.

The ICU department developed an ICU comfort care QI project, comfort care guidelines, a physician template note for comfort care, and a comfort care order set. The VA Palo Alto ICU group responded in a constructive fashion to potentially severe allegations and demonstrated a willingness to share with the health care community a very difficult situation. This transparency is leading to better care for patients there and with the publication may improve the care for other patients dying in ICU's.

W. G. Kuschner, D. A. Gruenewald, N. Clum, A. Beal, S. C. Ezeji-Okoye (2009). Implementation of ICU Palliative Care Guidelines and Procedures: A Quality Improvement Initiative Following an Investigation of Alleged Euthanasia Chest, 135 (1), 26-32 DOI: 10.1378/chest.08-1685

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The American Journal of Critical Care has a study about the natural history of chronic rejection after lung transplantation, which they state is the primary cause of death in lung transplant patients after the 1st year post-transplant. This study is a single-institution case series which presents the natural history of the 60 patients (out of 300 total transplants) who developed chronic rejection over an 8 year period. 26 patients died during the time of data collection. Median survival or time to re-transplant was 31 months after the onset of chronic rejection. Yes that's not a particularly helpful figure, but given the reality that some of these patients can be 'saved' with re-transplantation, and thus the natural history of chronic rejection depends heavily on the availability and success of re-transplantion, that's the best info we have....

They had only sparse data on the circumstances of death for the patients who died: it appears most of them died in the ICU, and they note that end-of-life discussions were initiated by family members most of the time (at least for those patients on whom they had data). Overall a picture is painted of a very sick population who spend a tremendous amount of time in the hospital, and receive very intensive care right up to the point of death.

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Thorax has a randomized, placebo controlled trial of inhaled furosemide for dyspnea in patients with COPD. Specifically, it was a randomized, double-blind, placebo controlled cross-over trial of inhaled furosemide in 20 patients with moderate to severe COPD. Subjects (mean age 61 years; mean FEV1 45% of predicted) were given inhaled furosemide or placebo on two different days and then a bunch of tests were performed (spirometry, exercise capacity using a cycle ergometer, etc.) about 30 minutes after the treatment. The specific treatment was inhalation of a 4 ml solution containing 40mg of furosemide (10mg/ml) or saline placebo, nebulized over 15 minutes.

Results: there were minimal differences in spirometry findings between groups. Those receiving furosemide had some statistically significant but modest improvements in exercise capacity (could tolerate an extra ~1.5 minutes of exertion) and exertional dyspnea (~1 point on a 10 point scale). They performed several subgroup analyses: essentially there were no clear-cut predictors of who responded. Of note, there were 7 patients whose dyspnea improved with furosemide but whose exercise capacity didn't. The authors discuss the multitude of hypotheses as to why inhaled furosemide could be effective.

My gloss on this is that this is some supporting data for further studies, but it is not compelling evidence for adopting this, particularly in a 'palliative care' COPD population. The outcomes looked at here were exertional dyspnea under controlled conditions within a very short time-frame of receiving a single treatment - and the magnitude of the treatment effects was not great. This is not dyspnea at rest or a clinical setting which resembles real life. I know inhaled furosemide for refractory dyspnea has been discussed anecdotally in the palliative care literature: anyone out there using it or know of other research supporting its use, particularly in refractory/rest dyspnea (from COPD or other causes)?

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Palliative Care Nurse: "We got a new consult in the ICU. A 55 year old who has been on the vent for 4 weeks with platelets of 75, on levophed and hemodialysis."
Palliative Care Doctor: "Sounds pretty serious. I wonder how he is going to do?"

Have you ever faced this dilemma of prognostication? If so, there is a new prognostic test developed for just this situation. If you are asking yourself, "Where is the prognostic dilemma? I already have a pretty good idea of what is going to happen" then you can go to the head of the class.

A reader sent me a well-executed study demonstrating the development and validation of a prognostic scoring system. This NIH funded study from UNC, Duke, and ECU was completed over 4 years (3 for the development cohort of 200 patients and 1 for the validation cohort of 100 patients).

The researchers choose to study patients requiring prolonged mechanical ventilation (greater than 21 days), a population notable for a high mortality and symptom burden. The reason for the study was noble in trying to enable physicians to have an easy to use, highly specific prognostic score to encourage open discussions about prognosis with patients and surrogate decision makers. They cite two studies in the discussion for the severe lack of prognostic disclosure in critical care situations (12% and 40% (SUPPORT)). (Hint: get a palliative care consult)

They identify the four variables with the highest relative risk: Age older than 50y, vasopressors, platelets less than 150, and hemodialysis. Each is assigned one point to get your ProVent Score. (I give one point for cleverness on the name for the score!) A score of 3 or 4 indicates a roughly 95% one-year mortality risk and a 85% 3 month mortality risk. (Disclaimer:Read the study for more details before you take this information and apply it clinically.)

Do you find this score to be clinically relevant? Would you use it to inform your decisions/prognostic estimates? Would you quote it to the family or patient? How about discussing with other clinicians? Personally, I am not too sure it is clinically relevant. We rarely see patients on vents longer than 21d still in the hospital. They are often already at the long term acute care hospital. I plan to give it a try and see how it compares with my own clinical judgement and that of my peers.

The authors conclude:

"Simple clinical variables measured on day 21 of mechanical ventilation can identify patients at highest and lowest risk of death from prolonged ventialtion."

The best part about actually reading an article is you can come to completely different conclusions (beware quoting abstracts!). For me (and you if you have read this far) the take home points to this article are really hidden and have numerous implications:

for clinical care (to be further validated):

• 40-50% of patients on prolonged mechanical ventilation (more than 21d) will die in the hospital (i.e. consider a palliative care consult trigger to discuss prognosis)
• If you survive the hospital stay, your mortality is only 17% at one-year (Graph)
• If you have a ProVent score of 2 or more you have minimal chances at being alive and independent in all ADL's at one year.
  

for future prognostic studies:

• Obtain clinician estimates for survival as a measure to compare your calculated prognostic score. Otherwise you risk making a score that is no better than current practice (communicated or not).
• Condeming all clinical estimates of survival based on a small handful of poorly designed studies does not qualify statements like "we know that prediction of mortality by clinicians using clinical probability of ICU survival is not accurate." We have too much to learn about the practice of clinical prognostication to come to this conclusion.
  
• Inclusion of the prognostic score is vital as a core part of the research to be examined and discussed amongst peers.
• Clinically relevant prognostic time frames are important and are very situation dependent. Discussing the chance that someone may have a 90% chance of dying within 1 year or even 3 months is not typically being discussed in ICU palliative care family meetings. The range may be hours, days or maybe a couple of weeks.
  

and for ICU studies of mortality:

• Include palliative care consultation and decisions to withdraw or withhold key life support measures as baseline demographic or outcome variables. These two issues could have major repercussions on validity of data sets concerning mortality.
• Consider using the ProVent score to stratify different risk groups in this select patient population.
  

(HT: B. Arnold)
Carson, S.S., Garrett, J., Hanson, L.C., Lanier, J., Govert, J., Brake, M.C., Landucci, D.L., Cox, C.E., Timothy, S.C. (2008). A prognostic model for one-year mortality in patients requiring
prolonged mechanical ventilation. Critical Care Medicine, 36(7), 2061-2069. DOI: 10.1097/CCM.0b013e31817b8925

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Being familiar with other medical blogs is a great way to keep up on how other doctors and nurses approach care for the dying. In fact, many of the most popular posts always seem to involve frustrations of medical futility, or the emotional impact of caring for dying patients. The range in tone for these posts is quite wide, from derogatory and demeaning of patients and families to eloquent and demonstrative of the great compassion in medicine.

A recent post by the anonymous blogger, the Buckeye Surgeon, highlighted his surgeon's view of palliative care. I came across the post from Kevin MD, a popular medical blog aggregator. Here is how he highlighted the post:

"Unrushed on his journey toward death"

Well put. That should be the goal of palliative care.

Seeing a palliative care post got me pretty excited. As I read the post I was glad to see a surgeon espousing viewpoints on palliative care areas. The Buckeye Surgeon highlights how many elderly patients with very devastating injuries may be able to get to surgery but have many co-morbidities that prevent recovery. With much wisdom, it is pointed out that seeing the few who do really well should not blind one to the many who do not recover.

In reading the post, it appears the surgeon may not have access to an involved palliative care team. I am very glad to see the mindfulness of palliative care, but there are some misconceptions to be addressed.

The post highlights that terminal extubation is something this surgeon actually forbids from happening in the orders:

-DNR-CC
-Do not extubate
-Morphine 4 mg IV q 15 minutes
-Propofol drip titrated to complete sedation/unconsciousness
-Turn down the sound on all monitors.

(DNR = Do Not Resuscitate CC = Comfort Care.)

There are times when extubating a patient can cause more distress - an obstructed airway, a high risk for hemorrhagic bleed, inability to control tachypnea with medications, feel free to add others. But in my palliative care reading and experience, leaving a patient intubated is the exception, and not the rule. So I was very surprised to hear this approach of keeping patients intubated.

Have any Pallimed readers run into this with consulting physicians? My guess is probably not a lot, because these physicians may not consult palliative care as they would not want a palliative care team to extubate their patient.

Good point of using morphine every 15 minutes as that fits with the knowledge of the T-Max of the concentration after an IV dose, but it is not specified as a PRN, so is it scheduled? Many palliative care providers advocate for a combination of opioid drip and rescue bolus to anticipate dyspnea.

Instead of turning down the sound of the monitors, most have the ability to be turned off in the room and continue monitoring at the staff station. This also avoids the constant monitor watching in addition to having unnecessary alarms.

So why does the surgeon advocate leaving a patient extubated? Basically because it is more comfortable. It is explained in the post with the following passage:

...it isn't ethical to merely "turn everything off". They've decompensated beyond the stage of self-sustaining life. Unplugging everything and stopping all the drips is about as cruel a thing as I can imagine. I never terminally extubate a patient. There's nothing more gruesome than watching a patient suffocate after terminal extubation. A wise old nurse made me experience it when I was a resident. No reason to pull that tube out. The dead bowel or the fecal peritonitis is going to stop the heart soon enough. No reason to expedite the death with unnecessary agony.

I agree with the blogger that it is unethical to be cruel, but I disagree that terminal extubation has to be gruesome, cruel, or cause suffocation or agony. There are reasons to pull that tube out. Not prolonging suffering is probably the most common reason given for extubation. Not continuing aggressive measures when you can no longer reach the goals set by the patient, family and medical staff is another reason.

Euphemisms and broad generalizations about withdrawal of life-support technologies are common with families, patients and medical staff, especially for the ability to make difficult situations more tolerable. 'Pull the plug', 'turn everything off', 'take him off the hook', 'stop treating her', 'withdraw care.' One role for a palliative care team is to highlight all the things that are being done for comfort, for emotional support to patient, family and staff, to prepare for death, to conduct religious and family traditions, to reminisce.

Many palliative care providers have worked in ICU's with dying patients and are therefore very familiar with the very involved process of terminal extubation of a ventilated patient. In palliative care, extubation is elevated to a procedure not just an order written for the respiratory therapist. Terminal extubation can be done well with a team approach, managing expectations, and aggressive symptom control for dyspnea and anxiety. Check out some of our 31+ posts on palliative care and the ICU to see some studies that talk about common ICU dilemmas.

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Many items....

1)
From JAMA:

First is one in their ongoing series 'perspectives on care at the close of life' on palliative care for patients with head & neck cancer. Besides being a solid review of the topic, as are most of the 'perspectives' pieces, this one stood out for two reasons. It's the most 'supportive care-y' one in this piece, and really reflects a broad perspective of palliative care as not just for the dying (despite the name of the series). The other is this wonderful (and rarely seen in the medical literature) discussion of self-image and blame:

Although some patients may blame themselves and feel they caused their own illness, patients may also feel guilt about the toll that the illness takes on their family and caregivers. Eating is a major social, cultural, and religious ritual in society, and patients with head and neck cancer often cannot participate in this activity. Even going out to dinner can become an impossible task, and patients may often be concerned about the impact this has on their family. Likewise, facial disfigurement—even if only temporary—may make it emotionally difficult for patients to leave the house, which can change the dynamic between patients and their loved ones. Feelings of guilt and self-blame in patients with head and neck cancer are therefore not only related to their own role in their illness but also to the belief that they are to blame for the impact the illness has on the quality of life of their loved ones. Physicians can assist patients with these feelings by encouraging them to talk about them with their loved ones, and even facilitating these conversations. For example, if a patient is accompanied to an office visit with a caregiver, the clinician can ask both of them, "What role has the illness taken on your relationship?" or even more directly, "Are you finding it difficult to eat out in public? How are you handling the changes imposed by the cancer on your social life or religious practices?"

The same issue also has a 'coda' for a previous perspectives piece about nausea and vomiting from last year.

And on the general cancer front JAMA also recently published the results of a randomized, controlled non-blinded trial comparing chemoembolization with radiofrequency ablation with both in patients with hepatocellular carcinoma. The study involved ~290 patients with unresectable (but not metastatic) hepatocellular carcinoma, at least one lesion greater than 3cm (as well as certain other tumor-specific entry criteria) & they were randomized to one of the 3 arms. I'm mentioning the trial for a couple reasons. First, there aren't too many therapies out there which have been shown to significantly improve survival in these patients and second, the study provides some general prognostic information for outcomes in this population: median survival was 24 months in the chemoembolization group, 22 months in the RFA group, and 37 months in the combined treatment group; 1, 3, and 5 year survivals were 75%, 32%, 13% in the chemoembolization group (very similar to the RFA group) and 83%, 55%, and 31% in the combined therapy group.

I'm curious how many other palliative clinicians are seeing these patients - my group sees a good number of them (usually referred by interventional radiology) as they near the end of their treatment course (or earlier if they're having a lot of symptoms) - and some relatively solid prognostic data are helpful.

2)
Archives of Internal Medicine has a research letter furthering the Vitamin D For Everything consensus that seems to be gathering in the last several years (falls, frailty/muscle weakness, cancer prevention, cancer therapy, and chronic generalized pain are just a few topics off the top of my head that vitamin D has been shown/purported to impact). This is about vitamin D for neuropathic pain; the letter presents uncontrolled observational data from giving 50 patients with painful diabetic neuropathies (and low serum D levels) ~2000 IU of vitamin D for a few months. The pain got quite a bit better. This is swell, and hypothesis generating to be sure - clearly controlled research is needed.

3)
Two from Journal of the American Geriatrics Society:

First is one looking at 6 month mortality after hospitalization for a COPD exacerbation. This was a single institution (Italian) prospective cohort study of ~240 elderly inpatients (mean age 82 years) with COPD exacerabations who were followed for 6 month mortality. For some reason patients with a previous history of 'chronic hypoxia' were excluded (???). Of note, the study cohort had 'nonacidemic' exacerbations which they defined as an arterial blood pH of greater than 7.34 (they don't clarify if they also excluded chronically hypercapneic patients who had high pCO2 but weren't actually acidemic). 2% died during the hospitalization (seems a touch low to me, given the age of the cohort) and 20% died by 6 months. They found a lot of the usual suspects were associated with a higher chance of death at 6 months (low BMI, poorer performance status, greater severity of COPD exacerbation) in univariate analysis. (None of the data were robust enough or presented in a way to affect clinical decision making, however.)

The one particularly interesting finding was that the functional status (measured via the Barthel Index) at the time of discharge (not at baseline) was predictive of 6 month mortality in the multivariate analysis - the authors comment on this too as it suggests (maybe) that the 'functional hit' one takes during the exacerbation is of particular prognostic importance. This makes sense but it's the first time I've seen it show up and I hope the authors/others look into this.

The other one is really for the prognosis completists out there: it looks at long term survival and functional outcomes for elderly patients who have already survived 1 year after 'planned or unplanned surgery or medical intensive care unit treatment.' Why one would want to study this exact population (both unplanned surgery or MICU stay? already survived one year?) remains unclear to me. Most people were doing fine, but of course they were since they'd already lived a year....

4)
Journal of Trauma has a paper looking at outcomes in elderly patients who suffer cervical spine fractures. This is a retrospective review of a single trauma center's experience with these patients. I have encountered only a very few elderly patients with cervical spine fractures (at least high C-spine ones) who have done well so this paper caught my eye. Acute mortality was ~25%, higher for high C-spine injuries and for those presenting with neurologic deficits (40-50% range). They also looked at the role of having an advance directive (they don't specify at all what they meant by this - POA forms, living wills, treatment limitations or not, etc.) and found that overall hospital length of stay was about 6 days shorter for these patients (despite having worse injury severity scores). They speculate that it may be because these patients' care goals were more palliative focused and so didn't linger in the hospital too long (although their ICU length of stays were identical to patients without ADs). Perhaps, but having an advance directive may also be a marker of increased family/social support, or preexisting nursing home residence, or other factors which could shorten a hospital stay....

5)
Resuscitation has a letter about the (what sounds like informal) development in one Canadian institution of "Do not MET" orders (MET being medical emergency team which sounds like what are frequently called rapid response teams in the US - essentially teams called in to rapidly assess/stabilize/transfer 'crashing' hospitalized patients prior to the patient needing a full 'code' called). It sounds like the MET team is still called even if a patient has a DNR order and so for appropriate patients people at their institution are writing, essentially, 'Do Not MET' orders as well.

If you found the 'METuscitate' in the title unbearable I'll point out that it's from the title of the the letter and I didn't make it up. It got me thinking, however, what does one actually call such a word? Is it a portmanteau? If so, how does one account for the acronym?

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Editor's note, evening of 4/23/08: my original post from yesterday went out garbled (a couple paragraphs were missing). I've fixed it as best I can (see the comments on this post). --Drew.

1)
The European Journal of Pain has a randomized trial comparing long acting morphine with transdermal fentanyl or methadone as the initial long-acting drug in cancer patients. This was a prospective, unblinded study of ~100 Italian cancer patients (mean age ~60 years) who had ongoing moderate to severe pain (mean baseline pain scores were 7/10) on weak opioids. (It's unclear what the baseline opioid use was in these subjects - without the paper explicitly saying so one has the impression that the group doing the study used a standard 'WHO Pain Ladder' protocol and these patients were ones who were having ongoing pain despite 'weak,' 'step 2,' opioids. Doses of at least 300mg of tramadol and 180mg a day of codeine were mentioned in the methods section.) They were randomized to 60 mg daily of morphine ER, 25 mcg/hr of TD fentanyl, or 5 mg q8hours of methadone (i.e. a methadone:morphine ratio of 1:4). Doses were then adjusted without any specific protocol (the group's own usual practice was used): for better or worse this study measures one center's 'real-life' experience after the randomization. Break through medication was morphine at about 1/6th of the 24 hour morphine equivalent dose of the long-acting med. Data were collected for a month. An 'intention to protocol' analysis was used: if you know what that means exactly please leave a comment - as far as I can tell it means an intention to treat analysis and they analyzed patients based on initial randomization even if their opioids were switched mid-study for clinical reasons. The study was powered to find a 30% difference in pain intensity.

Findings are easy to summarize:
All groups looked very similar throughout the four weeks (took 2-3 days for doses to stabilize; pain had reduced to the less than 4/10 level at week one and stayed there; side effects were similar). Fentanyl, which has found to be less constipating compared to long acting morphine in previous trials, was not found to be so in this one (although it wasn't necessarily powered to do this).

Two other findings to comment on. First the opioid escalation index was lowest for methadone (not surprising) but was highest for fentanyl (essentially those randomized to fentanyl needed a larger dose increase over the 4 weeks of the study compared to the others). The most obvious suggestion for this is that their chosen equivalent dose of fentanyl (25mcg/hr = 0.6mg fentanyl a day = 60 mg of morphine a day) was too low.

The other one is that these findings seemingly contradict another randomized trial comparing morphine ER with methadone as the initial long-acting opioid (which found that methadone was poorly tolerated compared with morphine and not a better analesic). That study used a methadone:morphine ratio of 1:2 to start off with, and was also starting patients on long-acting drugs relatively earlier - using 30 mg daily of oral morphine instead of 'waiting' until they needed 60 mg. It also used methadone as the break through drug in the methadone arm. These are sufficient differences to make comparison of the studies difficult. I have used the earlier article as a(nother)** reason not to use methadone as a first-line agent but the current study suggests that using this lower, initial ratio may improved methadone's tolerability as a first-line 'strong' opioid. I'm curious as to what others think of this.

**Other reasons for not using it as a first line drug: complex drug-drug interactions, QTc prolongation which is a particular concern in my patients with prolonged prognoses, complexities of transitioning someone off methadone onto another opioid if needed, ongoing lack of head-to-head evidence that it provides any clinical benefit over other opioids, and a general impression that the psychiatric side effects of methadone are worse than with other opioids (sleep disturbances, bad dreams, hallucinations). (That last point is completely a personal impression and not based in anything else.)

MERCADANTE, S., PORZIO, G., FERRERA, P., FULFARO, F., AIELLI, F., VERNA, L., VILLARI, P., FICORELLA, C., GEBBIA, V., RIINA, S. (2008). Sustained-release oral morphine versus transdermal fentanyl and oral methadone in cancer pain management. European Journal of Pain DOI: 10.1016/j.ejpain.2008.01.013

2)
Briefies:

a) The American Thoracic Society has released a policy statement on palliative and end-of-life care for patients with respiratory illnesses and in ICUs. Compared to a lot of society statements this one is somewhat of a tour-de-force in its scope and length - a good one for the teaching file. I loved these sentences:

'Families should be informed in advance of agonal breathing so they can view it is as a part of the dying process rather than a sign of patient discomfort. If one uses the term "agonal breathing," one should help the family to understand that it does not imply that the patient is in agony.'

They perhaps should have just recommended not to use the word 'agonal' in front of families altogether.

b) The latest issue of Journal of Clinical Ethics has a case discussion on Jewish law/ethics and artificial nutrition at the end of life (there are a handful of associated commentaries also - links to them are available from the PubMed citation linked-to above). This is the best commentary (from a medical perspective) on this that I've seen since I've been looking and is a good discussion of the issues involved, their history, and conflict resolution surrounding them.

c) Pain Medicine has a review about methadone's drug interactions. It's lengthy and the most comprehensive overview of the topic I've run across.

d) Pain has an editorial about efforts to get transmucosal fentanyl approved for 'breakthrough' pain for chronic non-malignant pain which is really an editorial about what is actually meant by breakthrough pain, and cautions against extrapolating from cancer pain research to CNMP.

e) BMJ has an article describing what the authors describe as the 'co-development' of palliative care and the right to euthanasia in Belgium, which is directed directly at those who worry that the growth of euthanasia would limit the development of palliative care. Their conclusion is that both 'movements' occurred together in Belgium and have shared some synergy (and common 'workers'):

Within Belgium we found few professional stances contending that palliative care and legalisation of euthanasia are antagonistic, no slippery slope effects, and no evidence for the concern of the European Association for Palliative Care that the drive to legalise euthanasia would interfere with the development of palliative care. Rather, there were many indications of reciprocity and synergistic evolution.

My assumption is that this is in BMJ as a debate-sparker as the UK considers 'assisted death' legalization.