Network Five Emergency Medicine Journal Club

In this interesting episode, we first explore if dexmedetomidine has a role in managing hyperactive delirium at the end of life. Then we discuss the toxic effects of immune checkpoint inhibitors (that are used to treat a variety of malignancies) and, finally, we learn about the concept of frailty and review some tools that can be used to assess it. This month's interlude segment will be presented by medical oncologist Professor Nicholas Wilcken.

Show Notes

Medical Oncology.

Professor Nicholas Wilcken, Sarah Rashid, Bratati Karmakar, Harry Hong, Dr Pramod Chandru, Shreyas Iyer, Caroline Tyers, and Kit Rowe.

Discussion 1:
Thomas, B., Lo, W., Nangati, Z., & Barclay, G. (2021). Dexmedetomidine for hyperactive delirium at the end of life: An open-label single-arm pilot study with dose escalation in adult patients admitted to an inpatient palliative care unit. Palliative Medicine, 35(4), 729-737. 

Presenter -  Sarah Rashid, physician trainee at Westmead Hospital. 

  • Terminal agitation and delirium are difficult to define and even harder to design studies around which to improve its management.
  • The current treatment algorithm advises the use of neuroleptics, benzodiazepines, opiates, and barbiturates; often at the cost of wakefulness and interaction with loved ones.
  • Dexmedetomidine can provide rousable sedation, a decreased severity of delirium, analgesia, a decrease in secretions, and potential anti-emetic effects. 
  • The aim of this study was to describe a potential reduction in delirium and the presence of rousable sedation with dexmedetomidine in palliative care patients suffering terminal delirium, with a secondary aim to determine whether reduced opiate requirements were observed.
  • There was a reduction in delirium (as measured by MDAS scores).
  • Almost 50% of patients crossed over to routine care, with 27% of these due to family request for deeper sedation. 
  • 15 of the 22 patients required an increase in opiate dosing, however, there were no negative survival benefits and there was a notable reduction in the use of other PRN medications (such as, for secretions). 
  • Ultimately, this pilot demonstrated promise for the use of dexmedetomidine in these patients (and prompts the need for further research in this area). 
Take-Home Points:
  • There is minimal evidence even behind our standard of care for these patients (midazolam, neuroleptics, and barbiturates). 
  • This paper encourages us to think laterally about what medications can be used for these patients. 
  • Terminal delirium is distressing for patients and their families, and at present, our treatments provide comfort but at the expense of wakefulness and interaction.
  • More research needs to be done into agents such as dexmedetomidine which could allow for a better-sedated experience.
  • More research also needs to be done into the experience of the dying process for patients and their families. 
  • Families have large effects on the management of dying patients, and thus there is limited value in doing a study without measuring outcomes for both the patients and their families. 

Discussion 2:
Wang, D., Salem, J., Cohen, J., Chandra, S., Menzer, C., & Ye, F. et al. (2018). Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors. JAMA Oncology, 4(12), 1721.

Presenter - Harry Hong - ED senior resident medical officer, at Westmead Hospital.

  • This study looks at immune checkpoint inhibitors targeting cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death-1/ligand-1 (PD-1/PD-L1). 
  • There is increasing use of these agents individually and in combination for various cancers.
  • This paper looks at multiple databases and analyzed data to characterize the rare but fatal side effects of these drugs. 
  • 613 fatal adverse effects were described: 193 associated with ipilimumab (anti-CTLA-4), 333 with anti-PD-1/PD-L1, and 87 in combination therapy (most commonly for the treatment of melanoma and lung cancer).  
  • The type of fatal adverse events differed between the treatment groups; with ipilimumab monotherapy associated mostly with colitis (70% of adverse events) compared with anti-PD-1/PD-L1 monotherapy where adverse events were more varied (colitis, pneumonitis, hepatitis) and combination regimens where there were additionally increased rates of myocarditis and myositis. 
  • The highest fatality rates were seen in myocarditis. 
  • The multicentre analysis also revealed the median time to onset of disease following commencement on therapy was 40 days with monotherapy and 14.5 days for those on combination treatment. 
  • Interestingly, the median time to steroid use for these patients was 5 days (suggested to be due to difficulty recognizing the diagnosis in these patients). 
Take-Home Points:
  • These drugs for some cancers have completely revolutionized treatment (they are not going away!). 
  • It is important to remember that the rate of fatal adverse events with these agents is still very low (particularly when compared with other oncology treatments). 
  • This data gives us information for what to be vigilant for when caring for these patients (particularly those presenting with non-specific symptoms and recent commencement on these agents). 
  • Take colitis seriously; it can be fatal. 
  • We are all learning; this is a new class of drugs with completely different toxicity to what we are used to – if in doubt ask the medical oncologist! 

Discussion 3:
Biganzoli, L., Mislang, A., Di Donato, S., Becheri, D., Biagioni, C., & Vitale, S. et al. (2017). Screening for Frailty in Older Patients With Early-Stage Solid Tumors: A Prospective Longitudinal Evaluation of Three Different Geriatric Tools. The Journals Of Gerontology: Series A, 72(7), 922-928.

Presenter - Bratati Karmakar, physician trainee at Napean Hospital.  

  • Frailty is a concept or syndrome which lacks a unified definition.
  • It is broadly defined as a vulnerability to stressors such as illness or treatment, which may aid in patient prognostication. 
  • Currently, there is no single standardized frailty assessment tool to guide our clinical practice. 
  • The presence of frailty has been associated with increased mortality, increased frequency of hospitalizations, intolerance to treatments, and a reduction in quality of life.
  • Data suggests that we as clinicians at the bedside are not accurate assessors of patient frailty.
  • This study compares well-established (however cumbersome) frailty scores; the Balducci frailty criteria and the Fried frailty criteria, with the Vulnerable Elders Survey (VES-13) which may be easier to use and apply in the emergency setting (requiring only self-reported data from the patient). 
  • The outcomes measured were functional decline (or loss of an ADL) and mortality.
  • 17% of patients were classified as frail using the Fried frailty criteria, and 25% when looking at the Balducci criteria and the VES-13.
  • The Fried frailty criteria and the VES-13 both showed that the probability of a functional event was higher in the frail group (with time to functional decline being 13 months in the frail and 36 months in the non-frail group using the VES-13). 
  • Regarding mortality, all 3 tools demonstrated prognostic value for overall survival.
  • Thus, according to this study, the VES-13 can be used to predict mortality and functional decline.
  • However, there was poor concordance between the three tools, suggesting that no single tool can currently be utilized to establish frailty (only 9% of patients were frail in all 3 evaluations).
Take-Home Points:
  • Recognizing frailty is important and it can be conveniently assessed at the bedside with tools such as VES-13 (but standardized frailty assessment tools need to be developed). 
  • Comorbid conditions do not indicate the presence or absence of frailty in isolation.
  • Physical disability is not a reflection of frailty. 
  • Whilst frailty increases with age, it is not a consequence of aging. 
  • Shared language is important for information to be clinically relevant. 

Interlude Segment:
Presenter - Professor Nicholas Wilcken.

The discussions were mediated by medical oncologist Professor Nicholas Wilcken and ED consultant Dr Pramod Chandru. 

This episode was produced by the ­­­­Emergency Medicine Training Network 5 with the assistance of Dr Kavita Varshney and, Deepa Dasgupta. 

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See you next time,
Caroline, Kit, Pramod, Samoda, and Shreyas.


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This is a podcast designed to bring exciting emergency research to you!