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by Shannon Haliko

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

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

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

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

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

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


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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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by Kristina Newport, MD

As we care for patients with serious illness, we frequently encounter depressed mood. Multiple studies have shown depression independently contributes to morbidity and mortality, and yet most of us do not systematically screen for it. This is again illustrated in Lloyd-Williams’ et. al recent study of 629 patients with advanced cancer attending palliative care day centers in England. Patients in this study identified as moderately to severely depressed on the PHQ-9 died three weeks sooner than those with no or only mild depression. A similar result was identified in patients who reported consideration of self-harm. Notably, in the majority of cases, involved health care providers did not know of their patient’s self-harm thoughts.

I don’t think this is unique to palliative care centers in England. The complexity of differentiating depression from symptoms of serious illness interferes with diagnosis. (See Fast Fact #7 - Depression in Advanced Cancer ). We, as a field, have not yet decided upon a simple tool that can be used to screen for depression or standardization of when it should be completed. (Although some helpful suggestions are found on Fast Fact 146 - Screening for Depression in Palliative Care ). Also, it can be a helpless feeling to identify a depressed patient when their treatment options for the depression may be very limited due to short prognosis and multiple, irreversible, contributing factors.

So while there is no simple answer to this challenge, I tend to think that we can do better with our current tools. Any effort is better than no effort, right?

In our community cancer institute, we recently began standard administration of the NCCN Distress Thermometer with all new patients. Any patients who had a score of 4 or greater were referred to appropriate support services. Like the Lloyd-Williams’ study, we uncovered distress which the health care team had not previously identified, resulting in a 47% increase in referrals to support services, the majority of which were related to “emotional problems”. While studies to validate the NCCN Distress Thermometer as a depression screening tool have had conflicting results, I can’t help but think that the 745 more people who were referred for increased assessment and assistance would not care about sensitivity and specificity. I can’t prove it yet, but maybe some of them had improvement in their mood and maybe they even lived a day or two longer as a result. I’m just glad that there is a tool out there that is palatable to oncology practices so they are willing to use it, in a standardized way.

Our next steps are to identify what to do with the information we find. What happens when we do refer patients? Do depressed patients live longer if they get treatment? With estimates of 15-50% of palliative care patients experiencing depression, we should figure this out.

But first, we have to ask them about it.

Kristina Newport MD (@kbnewport) practices Hospice and Palliative Medicine in Lancaster, PA where she also spends time running after her children, 4 and 6.

Lloyd-Williams M, Payne S, Reeve J, Dona RK (2014). Thoughts of self-harm and depression as prognostic factors in palliative care patients. Journal of Affective Disorders, 166, 324-9 PMID: 25012448



Image credit: "Depression Ahead" by Christian Sinclair for Pallimed, Photo Credit: "Sad Eggs" by Christian Sinclair

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

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

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

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

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

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

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The radio show Wait, Wait....Don't Tell Me! has a weekly segment called "Bluff the Listener" during which a caller listens to three unbelievable stories and then guess which one of the three is actually true.  Much to my surprise, this week's "true" (yet unbelievable) story is about evidence that acetaminophen might relieve existential angst. (Here's a direct link to the audio segment.)

Julius Axelrod (Source: National Institutes of Health)

Really?  Good ole' Tylenol might relieve bothersome thoughts about the ultimate threat to our existence?  How could I not investigate this further, if only because the report threatens any conception I have of this meek anti-pyretic/analgesic. The title of the study from Psychological Science piqued my intrigue: "The Common Pain of Surrealism and Death: Acetaminophen Reduces Compensatory Affirmation Following Meaning Threat."  

The journal article describes two separate studies, but has a background section with some familiar sounding concepts to palliative care clinicians and others which are likely foreign.  The authors describe evidence which suggests both physical and social pain may activate the dorsal anterior cingulate cortex (dACC).  This area of the brain may serve as a "cortical alarm system" which is sensitive to any discrepancy in the environment (such as a new severe pain stimulus or perceived social slight).  The dACC has thus "been theorized to be the source of the unpleasant arousal associated with uncertainty and violations of expectations."  Indeed, the authors cite evidence suggesting acetaminophen may reduce activation of the dACC.

What about fear of death?  We'll get there, but first, the "Meaning Maintenance Model" which is useful for understanding the study:

""The Meaning Maintenance Model" focuses on people’s compensatory responses to violations of expectations, termed meaning threats. The model posits that any perceived meaning threat produces unpleasant arousal that often lies outside of awareness, and is nonspecific to the causal stimulus. This arousal arguably serves to prompt people to identify the source of the perceived discrepancy and, if time and cognitive resources are sufficiently available, to accommodate to the unexpected event....In many cases, however, it is not possible to resolve the violation, either because the problem is too complex or because the source of the arousal has not been identified correctly. When this occurs, people may respond to the arousal by affirming any available unrelated schema to which they are committed. These affirmations of intact meaning frameworks serve to dispel the unpleasant sense that something is wrong."

In other words, if there's a violation to meaning which is challenging to resolve (e.g. thinking about one's own death), a person might compensate by using cognitive resources to resolve an unrelated but easier to resolve challenge. At the heart of the hypothesis, the presence of a violation of meaning may influence how the person resolves the easier challenge.  The person may overcompensate in resolving the "easier" challenge if already presented with a violation to meaning that cannot be readily resolved.   How did the researchers test this hypothesis?


In one of the double-blind, randomized controlled studies, the participants received either Acetaminophen 1000 mg or a placebo pill orally.  After completing some filler tasks to allow time for the drug to reach peak effect, all participants were randomized to complete an essay on one of two topics: 1. What will happen to their body after they die and how they feel about it or 2. The experience of dental pain.  Dental pain was chosen because it's an aversive event but likely doesn't create an experience of "violated expectations" like imagining death might.

Subsequently, subjects read about a hypothetical arrest of a person accused of prostitution and were asked to set a bail amount (a "social judgment survey"),  an arbitrary task for most of us but one which isn't too challenging to think about.

The researchers found that of all the participants, the group which was asked to write about their own death after taking a placebo pill set the highest bail.  The difference between this group and the other groups was statistically significant whereas the difference between the other groups (including the death-writing/Tylenol-taking group) was not significant.  In other words, the death-writing/placebo-taking group "compensated" by punishing the accused person more harshly yet this effect appeared to be mitigated by acetaminophen.

Self-reported positive and negative affect did not differ between any of the study conditions, suggesting to the researchers that compensation/"meaning maintenance" is largely not a conscious process.

Included in the paper is another study using similar methods to test the same hypothesis but with different conditions.  They found similar results.  The authors point out that while Acetaminophen acts at the dACC, it also acts elsewhere, so no conclusion can be made about the neurophysiological basis of any effect.  

So, after being asked to reflect on death, participants in this study (who were students at the  University of British Columbia where the studies were conducted) inflicted a harsher penalty than normal, perhaps to compensate subconsciously for their inability to resolve the "violation" of thinking about their own death. Should your electronic medical record system now add "existential angst" as an indication for Tylenol?  Keep prescribing it for mild pain and fever, but there's nothing in this study which suggests added value of Tylenol for a patient facing a serious, potentially life-threatening illness. There's probably more relevance to defense attorneys who might consider asking potential jurors during voir dire if they have recently been diagnosed with a life-threatening illness (I suspect that's a stretch, too). 

What is the relevance of this study, then, to you, the curious Pallimed reader?

Cicely Saunders' concept of total pain and Eric Cassell's deconstruction of suffering are frequently cited in palliative care literature.  Both suggest a common pathway by which changes in a person's physical, social, psychological, and spiritual states might inflict the person.  I cannot remember coming across a proposed neurophysiological explanation of the phenomena- if one exists, I'd love to see it. The theoretical "meaning maintenance model" described in the article seems to resonate well with total pain/suffering as well as our attempt to intervene through palliation.

If the "meaning maintenance model" is real, what adaptive and maladaptive ways do people use in a subconscious attempt to compensate?  For instance, people cannot control the fact that they will die, but can exert some control over decisions about their healthcare.  What subconscious processes are at play as patients and their physicians navigate these decisions?

What palliative care interventions provide an avenue for people to compensate when faced with the "unpleasant violation of expectation" which can be associated with the imminent threat of death?  Of many possibilities, dignity therapy comes immediately to mind as a therapy which fits the model of "affirming an intact meaning framework" in a constructive manner.  What are the neurophysiological effects of dignity therapy?

In the context of this study, it's also interesting to reflect on the variation amongst people with respect to death anxiety.  Might this be explainable by differences in neurophysiology?  For instance, when faced with death, might a region of the brain (such as the dACC) become less activated in some people than others?  What affect could age have on the response of this region of the brain (e.g. does it become less responsive as we grow older, on average).  What about over the course of a chronic disease?

What about spiritual practices?  Might mindfulness or reflecting on a religious verse about death influence the reactiveness of the dACC? In a very brief search, I did find a few references to the dACC being thicker on average in those who meditate, and a growing body of evidence suggests the value of mindfulness for various physical and psychological symptoms. (My hypothesis: Look at the mirror on your medicine cabinet rather than inside the cabinet for a possible source of relief for death anxiety.)

Lots of questions.  Maybe, unbeknownst to me, some answers exist, though I suspect future career(s) could be formed around some of them at the intersection of neurophysiology, psychology, and medicine .  

@lfettig

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Case:

Ms Emma N. is a 32 year old woman with type 1 diabetes who underwent a living related donor renal transplant and a subsequent pancreas transplant. Unfortunately, both transplants were complicated by rejection and graft failure requiring re-initiation of hemodialysis in 3 years ago. Since that time she has suffered with constant, intractable nausea with multiple episodes of vomiting throughout each day. Her symptoms were initially thought related to diabetic gastroparesis but they did not respond to metoclopramide, erythromycin or pylorus muscle botulinum toxin injections. An electrical gastric stimulator was to be placed but was aborted when a gastric emptying study was normal. Extensive workup, including laboratory studies, endoscopy, CNS imaging and abdominal imaging, was unrevealing. She received little or no benefit from adequate trials of domperidone, prochlorperazine, ondansetron, oral granisetron, promethazine, trimethobenzamide, scopolamine, mirtazapine, dronabinol, pancreatic enzymes and a proton pump inhibitor.

She underwent voluntary admission to a psychiatric hospital for treatment of any possible contributing eating disorder without any improvement. She has had more than 40 admissions to the hospital for nausea and vomiting. A feeding J-tube was placed to maintain adequate nutrition in 2 years ago. She presented to the Palliative Care clinic for further management of her nausea and vomiting. After a complete history and physical, the etiology of her symptoms remained somewhat elusive. She had nausea before her transplant and it had resolved when the kidney was working then recurred when it failed so the final conclusion was that her symptoms may be due to a poorly defined metabolic process related to her renal failure. Olanzapine was initiated on the first visit for refractory nausea and vomiting and the patient was referred to psychology and psychiatry to help with coping and to address underlying depression and anxiety. At the subsequent visit she noted some benefit so the olanzapine dose was increased and a granisetron transdermal patch was added. At the next visit her symptoms had improved dramatically with a clear temporal relation to starting the granisetron patch. She was only vomiting once or twice in the morning and was relatively asymptomatic through the day. In her first clinic visit she had vomited multiple times through the visit and appeared miserable.

At this visit she was asymptomatic, neatly dressed, wearing makeup and was thrilled at this new level of symptom control which was allowing her to re-engage her life.


Discussion: There were many factors that likely contributed to the dramatic improvement in Ms Emma N’s refractory nausea and vomiting. Better psychiatric care through the palliative care psychologist and psychiatrist almost certainly played a role in her overall clinical turn-around. The close attention, serial visits and supportive counseling she received in the Palliative Care clinic could also have been therapeutic. Up-titration of her olanzapine also likely was helpful. Olanzapine is an atypical antipsychotic that works on multiple receptors including dopaminergic, serotonergic, adrenergic, histaminergic and muscarinic receptors. Of particular interest is its antagonism of 5HT2 receptors which are located in the vomiting center and are not well targeted by other traditional antiemetics. Multiple small trials have demonstrated efficacy of olanzapine for chemotherapy-induced nausea and vomiting.¹ Many palliative care practitioners are now also starting to use olanzapine for refractory nausea and vomiting in patients with advanced cancer and other life-limiting conditions.^2-4

Even with all of these possible contributors to her improvement, there still seemed to be a clear benefit that came with initiation of the granisetron patch. While intravenous and oral granisetron have been available for some time, transdermal granisetron (Sancuso© - prescribing insert) is a relatively new addition to the practitioner’s toolbox for difficult to control nausea and vomiting. Transdermal granisetron was approved by the FDA for chemotherapy-induced nausea and vomiting (CINV) in September of 2008 based largely on a trial of 582 patients receiving multi-day moderately or highly emetogenic chemotherapy. Patients received either oral or transdermal granisetron and achieved equally good control of their symptoms with either method (approximately 60% in each group achieving complete symptom control). The most common side effect in both groups was constipation.⁵ The patch is an 8x6cm clear, plastic-backed patch and is worn for 7 days. Pharmacokinectic studies suggest that the patch delivers a dose equivalent to 2 mg of oral granisetron each day it is worn.⁶

It is thought to exert its antiemetic effect through antagonism of 5HT3 receptors in the gut and chemoreceptor trigger zone.⁷ Experience with the patch outside of CINV, however, is limited. This case suggests that transdermal granisetron may have a role in other cases of refractory nausea and vomiting. It is unclear why the transdermal form of the drug worked so much better than the oral version in this case. It could reflect absorption issues, especially if she was unable to keep the pills down. It could also reflect compliance issues and may bring into question the adequacy of her prior trial of oral granisetron. Whatever the mechanism, however, the result was dramatic. Further study of this agent in settings other than CINV is clearly needed. Hopefully these results can be replicated and other patients with difficult-to-control nausea and vomiting can achieve life-changing results similar to those achieved by this case.

References:
1. Navari RM, Einhorn LH, Loehrer PJ Sr, Passik SD, Vinson J, McClean J, Chowhan N, Hanna NH; Johnson CS (2007). A phase II trial of olanzapine, dexamethasone, and palonosetron for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier oncology group study. Supportive Care in Cancer, 15 (11), 1285-91 PMID: 17375339

2.  Srivastava M, Brito-Dellan N, Davis MP, Leach M, Lagman R (2003). Olanzapine as an antiemetic in refractory nausea and vomiting in advanced cancer. Journal of Pain and Symptom Management, 25 (6), 578-82 PMID: 12782438

3.  Jackson WC, Tavernier L (2003). Olanzapine for intractable nausea in palliative care patients. Journal of Palliative Medicine, 6 (2), 251-5 PMID: 12854942

4.  Passik SD, Lundberg J, Kirsh KL, Theobald D, Donaghy K, Holtsclaw E, Cooper M, Dugan W (2002). A pilot exploration of the antiemetic activity of olanzapine for the relief of nausea in patients with advanced cancer and pain. Journal of Pain and Symptom Management, 23 (6), 526-32 PMID: 12067777

5.  Boccia RV, Gordan LN, Clark G, Howell JD, Grunberg SM, on behalf of the Sancuso Study Group (2010). Efficacy and tolerability of transdermal granisetron for the control of chemotherapy-induced nausea and vomiting associated with moderately and highly emetogenic multi-day chemotherapy: a randomized, double-blind, phase III study. Supportive Care in Cancer PMID: 20835873 - Open Access PDF

6.  Howell J, Smeets J, Drenth HJ, Gill D (2009). Pharmacokinetics of a granisetron transdermal system for the treatment of chemotherapy-induced nausea and vomiting. Journal of Oncology Pharmacy Practice, 15 (4), 223-31 PMID: 19304880

7. Wood, G., Shega, J., Lynch, B., Von Roenn, J. (2007). Management of Intractable Nausea and Vomiting in Patients at the End of Life: "I Was Feeling Nauseous All of the Time . . . Nothing Was Working" JAMA: The Journal of the American Medical Association, 298 (10), 1196-1207 DOI: 10.1001/jama.298.10.1196




Pallimed Case Conference Disclaimer: This post is not intended to substitue good individualized clinical judgement or replace a physician-patient relationship. It is published as a means to illustrate important teaching points in health care.

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There was a time when I heard about chemo shortages, and I thought that must really force some tough choices for patients and physicians.  But thankfully (I thought) drug shortages for generic non cutting edge medications that have been around for a long time like the ones commonly used for symptom control would probably be relatively immune.

• Bedford discontinued lorazepam in May, 2011 to concentrate on the manufacturing of other products.
• West-Ward acquired Baxter’s lorazepam injection products in May, 2011. The company cannot provide a reason for the shortage.
• Hospira states lorazepam vials are on shortage due to increased demand. The 1 mL iSecure syringes were discontinued in September 2011.

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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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I thought I would post on what I hope will turn out to be an occasional series on sexuality here on Pallimed. We've covered sexuality some before. A post that leaps to mind is one by Christian in 2007 about the controversy that arose over a case where the staff at the world's first hospice designed specifically for young adults openly deliberated and decided to facilitate a 22-year-old patient's request to have sex before he died.

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If "palliative care" were a new chemotherapeutic agent, stockholders of the pharmaceutical company would be dancing in the streets today.  You can find the headlines everywhere:  From the New York Times ("Palliative Care Extends Life, Study Finds") to the Wall Street Journal ("Study: Advanced Cancer Patients Receiving Early Palliative Care Lived Longer") and as of the moment I type this, over 149 Google News search results.

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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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American Journal of Respiratory and Critical Care Medicine has a paper about the prognostic importance of delirium in ICU patients, and continues the thread of research we've been following recently about delirium and prognosis.

This study was a single-center (Yale) prospective cohort study of older (over 60 years) adults in an ICU, in which delirium was prospectively and rigorously assessed (by research nurses, using the CAM-ICU scale); ~300 consecutive eligible admissions were enrolled. They note that they included patients with 'coma/stupor' as delirious; I initiatlly assumed this implied patients who were spontaneously stuporous/comatose (due to a high grade encephalopathy from sepsis, etc.) as opposed to pharmacologically induced sedation/stupor. However as far as I could tell there were no such exclusions and these data apply to patients with delirium/coma from any cause. They basically looked at the number of days a patient was delirious/altered in the ICU, and correlated that with survival.

Patients (mean age 74 years, 31% with a diagnosis of dementia, 54% intubated, 82% received opioids or benzos in the ICU at some point, median ICU LOS 6 days, meidan hospital LOS 11 days, and median days of ICU delirium was 3). 16% of patients died in the ICU and 50% died by 1 year.

Yes, that's 50% 1 year survival for older patients admitted to an ICU, with or without delirium.

They did a mutlivariable Cox regression analysis and found that number of ICU delirium days were independently associated with shorter survival (hazard ratio); age, comorbidities, and severity of ICU illness were also independently associated with worse survival. Eye-balling median and 1-year survivals based on days of ICU delirium (this is me eye-balling a Kaplan Meier curve): median survival for ICU delirium lasting 5 days or longer was about 2 months with 1 year survival being about 35% for those with delirium 5+ days and 45% for those with 3-4 days. Patients without delirium did much better: 1 year survival was 75% (as far as I can tell the number of patients this represents is not shared).

This is further supporting evidence to the now vast pile of data indicating that delirium in multiple settings is a poor prognostic marker. To take these data at face value, being older, in an ICU, and having alterations in your mental status for more than 4 days implies a 50% 2 month mortality and 2/3 1 year mortality (and any ICU stay implies only a 50% chance of surviving a year). It's important to acknowledge that despite the good quality of the data collection for this type of research - prospective, used a validated assessment tool, all-comers were offered enrollment, etc. - it is still from a single institution and the absolute value of these numbers is not easy to generalize. That said, whether it's 2 months or 4 months or whatever: it's bad, and this study is as good as any recently to show that.

What do we do with this? I have always hummed and hahed about how to apply this sort of research at the bedside. We already know if you're 75 years old, and in an ICU, for any reason - it's a marker of high 1 year mortality. Which is not to say that you're likely to die in the ICU, and that going to an ICU isn't going to 'save you.' Most of these people survived the ICU, although most who had rocky ICU stays died within a few months. That, to me, is the real story - we can save you, but often for a relatively short period of time (and who knows what quality of life). Patients want to live, and be 'saved,' and all that good stuff, but we are doing them a disservice if we don't let them know that while we can 'save them,' and all that good stuff, it's usually not going to be for a long and healthy life. It's time to begin planning, and sorting through how you want to spend that time. A wise mentor once told me when talking about The ICU and older patients is that that the big question is not can this patient survive the ICU (most do and we have incredibly sophisticated systems in place to get people out of ICUs alive) but that can they survive it for what? And for how long? And while most patients want to live, knowing that they might be facing going through that again, and with likely little long-term benefit, many will choose not to do it again.

Anyway - the big etiologic question here, which may have a long term impact on how patients are treated, especially as pain and symptom meds do, indeed, cause/worsen/lengthen delirium, is whether the delirium itself causes the worse prognosis, or whether it's a passive marker of poor prognosis. If it's the delirium itself then anything to prevent or shorten it will make people live longer presumably: that will 1) hopefully be an impetus to actually do large/good trials of delirium treatment (in ICU and anywhere else - we need 'em), 2) raise the spectre of withholding symptom meds in hospitalized patients as they could be perceived as causing/worsening/lenghtening delirium and thus worsening long term prognosis?

(Thanks to Dr. Bob Arnold for alerting me to this.)

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Mayo Clinic Proceedings recently had a theme issue on opioids - all available in free full-text.

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First, and most practically, it has an excellent review of opioid metabolism (free full-text available). It's both detailed and readable, and one of the most useful single items I've ever read on this topic - and at the perfect level for the HPM fellow teaching file.

2)
Steven Passik has a review article on long-term opioid use for chronic pain - focusing particularly on aberrant drug use (different types of, screening and identifying, responses to, etc.). It's directed at general practitioners and very specifically tries to address all the different flavors of 'aberrant use': simple ignorant misuse, pseudoaddiction/undertreated pain, chemical coping, diversion, frank addiction, etc. and very much keeps the discussion reality-based: patients need pain relief, some benefit from opioids, for those patients with 'red flags' it can be extremely challenging to figure out what is actually happening. The paper is actually refreshing in its mundane discussion of opioid use for chronic pain - no hand-wringing about whether opioids are Good or Bad - just a dispassionate discussion of a mundane (insofar as commonplace) clinical problem.

3)
There's an article which reviews the literature comparing short acting with long acting opioids for chronic non-malignant pain. Summary: no clear benefit of one over the other (regarding analgesia, side effects). Not a huge surprise - the paper does have some academic interest for the wonkish in looking at the question.

4)
Finally, a review on physicians and chemical dependency - particularly focused on anesthesiologists and others with easy access to opioids and other abusable drugs (accompanying editorial here), which made me wonder if this could be a problem for physicians in hospice settings, where access to such agents is a little freer (compared to a hospital ward or outpatient clinic)?

Anyway - I thought this sentence would be appreciated by the spouses and co-workers of doctors everywhere:

'The intellect that physicians rely on to learn their craft allows them to develop exceptional rationalization, denial, and resistance techniques.'

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The International Journal of Eating Disorders has a case report and discussion of a patient with refractory anorexia nervosa who died receiving hospice care. This is one fascinating case report. The case, to summarize briefly, involved a young woman with a long history of anorexia nervosa, refractory to all attempts at treatment (including involuntary/forced treatment) who apparently also was not deemed a candidate for forced guardianship (the hospital's legal counsel advised she would not meet requirements to be declared incompetent).

This is how they describe the ethics committee's response to the case:

The committee’s members struggled to understand how one could die from a psychiatric illness (other than by suicide or unintentional overdose) and were not sure how to proceed. Although they could delineate the differences between acute mental health risks such as suicide, drug overdoses, psychosis or self-neglect, they had no points of reference regarding how to manage a patient who was chronically a danger to herself, unwilling to engage in further treatments, and unresponsive to all prior attempts to treat her involuntarily. The only examples the committee raised for comparison concerned drug users who received heart valve replacements, yet continued to use, knowing that such ongoing use would kill them. In such cases, if a high risk of ongoing subsequent IV drug use was suspected ahead of time, the decision was often made not to provide valve replacements, but there was no forced treatment.

This is how they presented what palliative care for anorexia nervosa would look like to the patient (italics mine):

If she chose to pursue treatment she would be assisted, but the staff would not force her into any involuntary placements or impose any treatment she did not want. There would be no weigh-ins, no calorie or exercise monitoring, no IM medications and no required therapy sessions. She would be offered outpatient therapy only as she felt desirable and necessary. Psychiatric medications would be prescribed as the patient deemed necessary to help manage depression, anxiety and insomnia. The patient would receive weekly visits from a palliative care nurse, who would work with her to manage her symptoms and keep her comfortable. The patient agreed to no further hospitalizations, but did not fully agree with the plan for ‘‘palliative care’’ since she did not believe she was going to die.

The patient basically continued her illness behaviors, got weaker/sicker, and was eventually enrolled in an inpatient hospice where she died.

Some observations.

1. AN is clearly at times a terminal illness, refractory to all attempts to reverse it.
2. In this case it was clear that the patient's life could have been prolonged although only with forced treatment. It was the opinion of her physicians that such forced treatment, while life-prolonging, would not 'cure' her AN (for some patients a trial, or many trials, of forced nutritional treatment along with psychiatric care gets them to the point at which they are willing to continue with voluntary treatment and can have a durable response; it was felt this would never happen with this patient). Thus the decision came down to trying to force further involuntary treatment vs. letting the disease run its natural course with her inevitably dying.
3. I found it interesting that they did not feel there was enough of a chance she'd be considered incompetent that they didn't even put her through the court process. Her statement that she did not think she would die (and it seems she continued that belief until the end, and persisted at least until she was enrolled in hospice in saying that she in fact wanted to live) seems to me to indicate such a fundamental lack of insight into her condition that I'm not sure I believe that. Granted, I'm not too familiar with criteria for declaring someone incompetent on psychiatric grounds, but I assume it has something to do with one's mental illness being such that one cannot even take in basic medical information.
4. That said, and even if she was legally stripped of her decision-making rights, for situations in which even involuntary treatment would not work long-term, is it right to force patients to do that? In this situation they concluded No, and made plans accordingly, which seemed to work as well as could be expected under the circumstances.

I have had, thankfully, only minimal involvement as a palliative doc with patients with refractory eating disorders. And while #1 is certainly true, these cases stick in your gut a little more than, say, refractory CHF or whatever. Part of that has to do with it being psychiatric illness, as opposed to medical, and the at least visceral differences that creates. I think it also has to do with the very fact that the illness precludes a patient from from having 'normal' insight and ability to make decisions, etc.: that's the very nature of the disease.... Youth, potential loss of decades of vitality, and the fact that there's a tiny chance that stripping a patient of all rights and forcing treatment for a long time might end up working, make it all the more distressing. I wonder how the hospice providers handled her care, emotionally?

And what if this was refractory depression, and a patient was suicidal? Depression can certainly be a terminal illness, and it certainly can become refractory to all treatments (drugs, involuntary committment, electroconvulsive therapy, etc. etc.); we are not offering them hospice care or 'palliative care.' Which I'm fine with (I'm not really sure what that would mean anyway other than not forcing treatment or stopping a patient from committing suicide), and part of this comes down to the difference between 'active suicide' from one's refractory depression vs. 'passively "allowing" oneself to die from an eating disorder.' But I think these cases really push these distinctions we make - make us really examine them. If the choice was permanent involuntary committment and ongoing ECT, when do you decide enough is enough? That rarely happens of course because patients either get better or commit suicide (given that long-standing involuntary committment is rare/unrealistic/often unable to be provided for financial or regulatory reasons for depressed patients).

Much more commonly than eating disorders I care for patients with other mental illnesses (such as schizophrenia with refractory symptoms/inability to comply with treatments despite efforts to control the schizophrenia) which preclude them from receiving what would otherwise be life-prolonging care (e.g. chemotherapy, dialysis, whatever). In these cases I tell my trainees what the patient is really acutely dying from is the schizophrenia, as it is precluding them from receiving life-prolonging treatment. That aside, while these cases are tough and tragic, I'm quite comfortable with them as long as everyone is in agreement that there's no reasonable alternative to providing life-prolonging treatment other than forcing it upon a patient who cannot understand it and could not receive it without ugly/inhumane restrictions (forced hospitalization, restraints, whatever). I'm asking myself why these eating disorder cases feel different to me and I wonder that, despite my flippant statement above that the patient is 'really dying of shizophrenia,' the difference to me is that they're also really dying of cancer, or renal failure, etc. as opposed to this case in which this young woman was dying, solely, of her mental illness...?

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1)
Pain has a paper about 'acceptance of pain' in cancer patients. They define 'pain acceptance' as: "the acknowledgement of pain without directing all efforts toward controlling it and refocusing efforts toward living a fulfilling life in spite of chronic pain."

The study involves ~130 patients at a single Canadian cancer center (mean age 55; ~60% saying that their worst pain during the day was moderate-to-severe) who answered a whole bunch of questions about pain, quality of life, etc.

They were also administered a pain acceptance scale which looked at activity engagement and pain willingness: "Activity Engagement measures the degree to which people with pain participate in life activities despite pain, and Pain Willingness measures willingness to experience pain without controlling it."

A shockingly-difficult-to-interpret (at least for me, and at least in part related to an exuberance of acronyms related to all the different scales used) regression analysis was then done to see what predicted more or less pain acceptance. So much so that I will just let them summarize their findings in their own words:

This is the first study to show that greater acceptance of cancer pain is related to better psychological wellbeing. ...This study is also the first to show a relationship between parental status and acceptance of cancer pain. Specifically, parents with children at home reported lower willingness to experience pain than those without children. Acceptance of cancer pain was unrelated to pain duration, severity, and qualities, subjective social and relational factors, and age and gender. This study adds to our growing understanding of biopsychosocial factors in cancer pain and its impact and suggests that acceptance may play a role in patients’ adaptation to living with ongoing disease-related pain. We found that Activity Engagement was related to lower severity of depressive symptoms, and Pain Willingness was related to less pain catastrophizing.

The finding that parents with kids at home had less 'willingness' was pretty solid and seems worth exploring. Regarding the other findings, I found myself asking why one couldn't conclude simply that people who were doing better (coping-wise) were doing better and they were simply measuring the same things (depressive symptoms as an index of activity engagement, catastrophizing as an index of willingness), as opposed to there being something unique/helpful about the idea of pain acceptance: particularly that pain acceptance didn't seem to have much to do with pain itself or function. For me, this is a good example of research which is tantalizing close to questions I grapple with as a clinician (What does it mean to be someone who copes well with their pain? Is that something 'real' and distinct from overall approaches to coping, psychiatric symptoms, or psychopathology? Is this a phenomenon which is amenable to clinical intervention separate from supportive counseling and good symptom control? etc.) but then disorients rather than clarifies....

2)
JCO has a paper describing the development and initial validation (in a geographically restricted sample) of a tool to measure patient satisfaction with care in advanced cancer patients. The tool was developed to measure satisfaction/identify needs based on the following assumptions of what quality care means for advanced cancer patients:

[H]ealth care providers sensitively communicate with patients about their prognosis and promote shared decision making to the extent that patients want to be involved; patients are educated about what they can expect during treatment, what to monitor, and who they can turn to for help; patients are provided with their desired emotional support and symptom amelioration; patients are treated with respect; cancer treatment sessions support comfort, ensure privacy, and promote healing; and care is coordinated among health care providers.

As you can see there is a particular focus on communication - the tool asks numerous questions about how communication went - and notably the area which patients most consistently identified need for improvement (over half) was regarding communication (as opposed to, say, how things went in the chemo-room, etc.). The validation data (internal consistency, etc.) looked promising.

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Meghan O'Rourke has written a series of articles dealing with the loss of her mother to colon cancer on Christmas day. I cannot recommend this series highly enough. She weaves a wonderful mix of humanities with the science of humanities, all on the background of her own loss experience. Here is a great snippet that gives you a sense of where she is at:

Since my mother's death, I have been in grief. I walk down the street; I answer my phone; I brush my hair; I manage, at times, to look like a normal person, but I don't feel normal.

She researches the medical literature, and thankfully finds the Yale study on Kubler-Ross stages/states from 2007. She makes many literature references including CS Lewis' A Grief Observed, Shakespeare's Hamlet, Sogyal Rinpoche's The Tibetan Book of Living and Dying, multiple poets and Joan Didion's The Year of Magical Thinking. She even talked with Holly Prigerson, the lead researcher on the Coping with Cancer study.

This series is a must read for anyone in hospice and palliative care. Use each article as a discussion point at your next team meeting. Feel free to post other ways to use these articles in the comments.

I will leave you with an untitled poem by Franz Wright she quoted in the second article:

I basked in you;
I loved you, helplessly, with a boundless tongue-tied love.
And death doesn't prevent me from loving you.
Besides,
in my opinion you aren't dead.
(I know dead people, and you are not dead.)

(HT to @doclake (Twitter) and the Hospice Foundation of America Blog)

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JAMA has published two Perspectives on Care at the Close of Life pieces in the last few weeks.

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The first is a review on palliative care for Latinos. With all due respect to the consistently excellent PCCL series I have to say this has been my favorite, perhaps for the simple reason that my own content-knowledge in this area is lower relative to the other ones. (This is despite doing my medicine training in Denver - I did not however learn about aspects of care particularly relevant to death and dying). Perhaps also because it is contains such well-written prose:

A young pregnant woman develops a fatal cancer and dies before her daughter reaches her first birthday. Her partner cannot bear the thought of her dying. The suffering experienced by this patient, her partner, and the health care team suffuses all of the care providers' descriptions of this case. The deep sadness here is universal. What is also clear is the profound influence of culture and immigration on this young woman's experience at the end of her life and on that of her partner.

The paper discusses important cultural norms/narratives such as familismo, fatalismo; barriers to care from language/interpretation (this is one of the best, short, practical discussions of using medical interpreters I've seen anywhere), and issues regarding religion and immigration status. This is now at the top of my teaching pile for cultural issues.

2)
The second is about self-care for physicians caring for dying patients. It focuses on burn-out and compassion fatigue, but also devotes a large amount of space for positive coping/responses to workplace stress, grief, and loss, and on the 'best-practices' of clinicians who thrive/endure in stressful environments full of loss.

The physician who formed the case for the piece made a comment which I really appreciated:

'The stuff that burns me out has nothing to do with loss. . . . It's fighting insurance companies . . .'

I think many who don't do palliative care assume the major stressor is the death/loss - for me and most that I've spoken with about this issue this is not the case (it's there of course, and there can be individual cases which are devastating, although routinely caring for dying patients and their families is invigorating and a source of great satisfaction). It's the grind of documentation, patient-load overload, administrative-academic-clinical duties pulling at you at once, etc. etc.

Along these lines, they discuss the enriching aspects of caring for the dying:

Posttraumatic growth is characterized by positive changes in interpersonal relationships, sense of self, and philosophy of life subsequent to direct experience of a traumatic event that shakes the foundation of an individual's worldview. Posttraumatic growth is not uncommon and may occur concurrently with negative sequelae of trauma. The term vicarious posttraumatic growth describes the phenomenon of clinician growth that results from witnessing positive sequelae of other people's experiences of trauma. This may include the clinician's feelings that his or her own life has been enriched, deepened, or empowered by witnessing the patient's or family's posttraumatic growth. When patients experience meaning and peacefulness in relation to their approaching death, this enriches the lives of the clinicians involved. This phenomenon appears similar to the "healing connections" identified by Mount and colleagues.