MIC CAVAZZINI: Welcome to Pomegranate Health, a podcast about the culture of medicine. I’m Mic Cavazzini for the Royal Australasian College of Physicians. Today’s episode is the second part of our discussion about delirium. In Episode 60 we talked about the presentations and screening of this deceptive syndrome, as well as the medical risk factors. Among the more common are dementia, infection and metabolic disorders like hypercalcaemica. Then add to this a host of drugs that can increase agitation, such as those with anti-cholinergic properties.
Just as important as these medical and iatrogenic factors, are a host of environmental triggers that are even more modifiable. Anything that contributes to a person’s disorientation and discomfort can increase the likelihood of a delirium episode. There’s no doubt that a lot of these factors are compounded in elderly and frail patients, but it’s important not to be fatalistic. In a great review titled “Responding to Ten Common Delirium Misconceptions With Best Evidence” the authors write that delirium is not inevitable and that each of the precipitants can be identified and improved in a systematic way.
Even at the end of life, delirium can be reversed in half of all patients, says my guest Professor Meera Agar. She’s a palliative care physician at Liverpool Hospital and chair of the IMPACCT clinical trials network. We were joined by Professor Gideon Caplan, director of Geriatric Medicine at Prince of Wales, and you’ll also hear from the resident bird life in the hospital grounds. Professor Agar explained how something as common as visual or auditory impairment is so often neglected in people at risk of delirium.
MEERA AGAR: So I think the core feature of delirium is inattention and changes in awareness of your environment, and we rely on our hearing and our vision to be attentive. So if you already have problems with attention, then if you’ve got impaired vision and hearing, that’s just going to exacerbate the problem. And so when you’re trying to improve all the cognitive reserves that someone has and keep them oriented to their environment and bring them back to the reality, you need all their senses that are working well to be optimised. And people don’t bring their hearing aids with batteries, or their glasses, or nobody remembers to put them on, and trying to find a hearing aid battery in hospital is like trying to find a needle in a haystack.
GIDEON CAPLAN: And they’re about the same size, nowadays.
MEERA AGAR: And people, they leave them at home to keep them safe. So there’s lots of reasons that those simple things are quite tricky and require a concerted effort, but can make a huge difference.
GIDEON CAPLAN: And also things more hidden, that sometimes they may not be able to communicate that they have this discomfort. And a classic case is for example constipation, that you mentioned before, or urinary retention, and they may not be able to tell you where they have discomfort, but just get confused. And that’s one of the features of particularly older patients, that they present atypically, they don’t come in and say “I can’t pass urine and I’ve got this pain in my lower abdomen”, they just start acting in a confused way, or might be hypoactive, and you have to be really looking for these problems to discover them.
MIC CAVAZZINI: Professor Sharon Inouye of Harvard Medical School, she’s best known for establishing a framework called the Hospital Elder Life Program, or HELP for short. This has been well validated in clinical trials. So one of her big things is sleep hygiene. How do you help aged care residents get to sleep at a regular time without drugs?
MEERA AGAR: I think sometimes in healthcare, we’re on shifts, so we’re just working as if it’s the daytime, so being noisy, having loud pagers. We go in and we turn the lights on because we need to give medications, and when you prescribe things –
GIDEON CAPLAN: We take obs in the middle of the night.
MEERA AGAR: – we just write the times on the chart, and we put ‘midnight’, and it’s like well, is that really necessary? Is there another option? Could we give it earlier? Do we really need to be taking our blood pressure for this person whose blood pressure has been stable for seven days at 2:00 am and wake them up? And simple things like making sure people are not having caffeinated drinks, and working with the patient to problem solve. And there’s been some lovely work in ICUs just in reconfiguring the work flows and the lighting and the way people operate in an ICU environment, which otherwise is just full on lights, noise, not at all built to be conducive to sleep.
MIC CAVAZZINI: Sharon Inouye also mentions having a natural light/dark cycle, the windows, warm milk and a back rub can help people get to sleep. I mean, are any of these protocols found in aged care in this country?
GIDEON CAPLAN: We’ve had a volunteer program based on the HELP program at my hospital for at least 15 years I’d say, yeah, and it really does help patients. And the staff on the ward feel supported, the patients enjoy the interactions, and the patient’s family are grateful that someone else is coming to visit their relatives when they can’t be there. So it’s one of those really win/win/win situations. But you do need a coordinator to run the program, and that does require some expense. But you save money by preventing delirium, which subsequently reduces length of stay in hospital.
MIC CAVAZZINI: Of course cognitive stimulation is also essential, card games, newspapers, Sudoku. Are either of you familiar with the reminiscence exercises that Professor Inouye is fond of?
GIDEON CAPLAN: Yes, so we have a ward for behaviourally challenging people, and we play music from the ’50s and ’40s, and movies from that time as well, which people recognise the music, and music has a way of connecting with people when you really can’t get through sometimes. And it’s amazing how it will make people feel better and calm people down. And there’s always a temptation when you have a radio or a music player on the ward that the nurses switch it to the music they really enjoy. And the patients can’t relate to hip hop, or those kind of things. So some appropriate music, people love it, and it really helps to settle people down. It’s amazing.
MEERA AGAR: And I think you want to make these kinds of activities as natural and authentic as possible. It’s not about just going in and saying “It’s Monday, eight o’clock”, and then off you go. There are some patients that just say “I’m not going to play Scrabble” or “I hate card games”.
MIC CAVAZZINI: Yeah, so I mean in a 2015 metanalysis, Sharon Inouye’s team reported that the HELP program reduced the likelihood of delirium incidence by more than half, and for falls the odds reduction was 60%.
GIDEON CAPLAN: That’s one of the fascinating findings of that metanalysis, because programs aimed directly at falls don’t reduce falls as much as programs aimed to reduce delirium. So it just shows that the underlying mechanism of especially injurious, but many other falls in hospital is delirium.
MEERA AGAR: And one of the concerns has always been about these kinds of programs, is that you’re trying to proactively mobilise people when they’re quite unwell, and that you’d actually increase the falls risk, and we couldn’t possibly have volunteers helping people ambulate around the ward when they’re elderly and frail and have a risk of falling. And actually probably if it’s done safely and well, it actually has the counter impact.
GIDEON CAPLAN: Yes, falls are much more caused by reduced mobility, as are pressure sores, deconditioning, other adverse consequences of decreased mobility which comes with delirium.***
MIC CAVAZZINI: Lack of support in mobilising is just one of the barriers to healthy care that nursing home residents can experience. A research group at the University of Exeter estimated that the average person living with dementia in British nursing homes receives less than 15 minutes of social interaction over a week.Across 24 care homes they implemented an educational program for staff to bump this up to an hour. Results published in 2018 in PLoS Medicine showed there were significant improvements in resident’s quality of life and agitation scores, and that the costs of the program were actually lower than treatment as usual. An nice vignette is that of one home where staff drew up chart of each resident’s individual interests, so that anyone on duty would know which bloke liked to talk about jazz, or who was in charge of the gardening club. It's important to note that delirium can recur over weeks or months, but that quicker recovery is associated with better long-term outcomes.
This wasn’t supposed to be another story about COVID-19, but in the New York Times, Sharon Inouye writes that she’s heard from colleagues all over the world about an increased incidence of delirium, up to 70 percent by some accounts. In Professor Inouye’s words, “If you could design a health care system that would generate delirium, you would design exactly the system we have with Covid-19: where patients are … deprived of human comfort and communication;…. where [staff] are instructed to minimize visits to patients’ rooms since protective equipment is scarce…. ; and where staffing shortages are so severe that nurses feel they can deliver only the bare necessities of care…” She also mentions that in stressed staffing conditions, there tends to be more reliance on pharmacological management.
And that’s what I want to talk about now. Just to illustrate this, let’s go back to the story of Adam Kwok from the last episode. Adam previously described how his 77 year old partner Claude experienced a bout of confusion after a femoral fracture repair in 2017. A year later, Claude underwent cardiac surgery and had a more florid episode that involved hallucinations and aggression.Soon after this, Claude went back into theatre for a spinal fusion but half-way through that operation, his heart was showing signs of distress and the operation was aborted. Once Claude’s blood pressure was stabilised he was transferred to ICU. It was a Saturday morning when Adam found him in pretty reasonable shape given what he’d just been through.
ADAM KWOK: So he woke up and then he was in good spirits, he certainly didn’t appear to be in pain, and I thought it was OK. I think in the evening he started again asking for his pants, and that’s never a good sign. After I left, and I went back the following morning, and they said he was very verbally aggressive during the night, so they had to put him on a high dosage of that dexmedetomidine that he was previously prescribed, and also on another tranquiliser, you know, quetiapine.
And then as the following day went by and they increased the dosage, to the point when I left him I think he was on the maximum dosage of both medications. And he was confused, he was drifting in and out of consciousness, so he wasn’t waving his arm in the air. And to me he wasn’t hallucinating, and that’s what I said to the doctors on duty. But they said “He’s a big man, he’s aggressive, and for his safety we’ve got to keep him on the maximum dosage”. And I could see the frustration, he couldn’t move, he couldn’t talk, he couldn’t really talk.
So when I went back in on the third day, he was stirring, and still maximum dosage, you know, quetiapine, twice daily. And I thought I’m going to put my foot down, and I said “Well, how about just dropping it to once daily and seeing what happens? Let’s try it. And I’m here all day, I’m going to take responsibility”. And the changes were so visible. He became more responsive, and he started being able to talk. And he actually said, used those words to me, he said “God, the fog has just been lifted”, it was really relief for him. And what he thought was, all this time, he was looking quite petrified, during this period, he actually thought he had a stroke. Because he was so heavily sedated, he couldn’t get his words out, and he just thought “What am I going to do if I’m going to be like this for the rest of my life?”.
And so they reduced the quetiapine to once daily, but he’s still taking that in the evening. And he started having complications of ileus, so there’s no movement in the guts. And he started throwing up, and they had to aspirate him with nasal tube, and it was pretty bad. And at that point he was transferred to the ward, and I requested to see a doctor, and here comes Gideon. I also asked would his quetiapine make the problems of ileus worse. And then he said yes, and so Gideon took that off the chart, and he started improving from there on, and so I’m forever grateful to Gideon.***
MIC CAVAZZINI: As Adam has described, Claude had been given dexmedetomidine in the intensive care unit, an α2-adrenergic agonist. This has become a go-to sedative in mechanically-ventilated patients especially, because compared to benzodiazepenes like lorazepam and midazolam, it doesn’t depress respiratory drive and is associated with significantly shorter stays in ICU. Benzos are also well-known risk factors for delirium, while early comparisons showed some evidence that dexmedetomidine was safer in this respect. More recently, two large and well-designed trials showed that patients receiving this sedative in ICU experienced delirium at less than half the rate of those given placebo. It’s still not clear whether dexmedetomidine has a protective effect of its own, or whether the treatment group simply benefited from more sparing use of other deliriogenic sedatives. And the theory that it helps cognitive reserve by enabling more restorative sleep is yet to be tested conclusively.
Finally, dexmedetomidine is only administered intravenously and patients need to be closely monitored for signs of bradycardia and hypotension. So while it is finding a place in the ICU, there is insufficient evidence to advise its use specifically for the prevention or treatment of delirium, according to the 2019 Scottish Intercollegiate Guidelines. In fact, they don’t support use of any psychotropic medication for prophylaxis, in line with the current NICE guidelines, and the Australian Safety and Quality Standards from 2016. A meta-analysis from that year which took in data from 962 post-operative patients found that antipsychotics had no significant impact in preventing delirium incidence compared to placebo.
And even for treating prevalent delirium, Meera Agar has written that the widespread use of antipsychotics over the last 40 years is not warranted by the evidence base. Of the seven RCTs that do report favourable outcomes for antipsychotic management of symptoms, she notes “one had flawed concealment of allocation, several were inadequately powered, and only 3 were placebo-controlled.” A 2018 Cochrane review paints the same picture about the “low or very low” quality of available evidence. From a pooled 494 participants the authors concluded that antipsychotic treatment did not reduce delirium severity compared to placebo or to a non-psychotropic drug. And second-generation antipsychotics were not shown to be any more effective than haloperidol, even though there were more participants pooled into that meta-analysis.
With all the variation in the design of previous studies and cohorts sampled, Professors Agar and Caplan undertook a large and well-controlled trial. Participants were recruited from 11 Australian hospices or palliative care wards, and on being diagnosed with delirium they were randomised to receive haloperidol, risperidone or placebo. Over 80 patients ended up in each group, and the blinding was second to none—right down to the identical pills in matching bottles shown to every patient. They were scored for delirium symptoms over three days, and it was found that both of the treatment groups actually had higher delirium scores than the placebo arm as reported in a 2017 article in JAMA. One year later, American researchers published equally compelling findings in the New England Journal of Medicine. In an even bigger cohort of patients experiencing delirium in critical care, IV injection of either haloperidol or the atypical antipsychotic ziprasidone did not significantly alter the duration of delirium episodes compared to placebo.
MEERA AGAR: And so the question we wanted to ask is well, in someone who has delirium at the end of life where it’s about trying to relieve the distressing symptoms, if anything we found that the symptoms that we were interested in were actually worse in the groups that received antipsychotics, rather than the placebo group that were receiving good supportive care, good assessment, and management of the precipitating factors. So the natural history of delirium, if you’re doing all of those other things, is to improve over time.
GIDEON CAPLAN: Mira’s study was a real landmark, because she took a very vulnerable population which had never really been studied in adequate numbers before, and she clearly showed that mortality was increased in people who were prescribed antipsychotics for delirium, which is a ground breaking finding. All the previous studies had showed no benefit, but she actually showed harm from prescribing antipsychotics. And while her study was ground breaking, it unearthed, when you’re talking about the standard of care around the world, that people came out with really bizarre reactions. Some people wrote letters saying “Oh well, you only prescribed this many milligrams of poison. You would have done better by prescribing four times as much poison, people would have done better then”, which goes against all the principles of pharmacology. So it really unearthed some of the misconceptions that are out there of standard practice in the community, which we need to stop, we can’t just keep doing the same thing and expect to get better results.
MEERA AGAR: And often the prescribing is by the most junior member of the team, or not even a member of the team, the junior doctor at 2:00 am who doesn’t know the patient, who is just responding to a highly agitated situation, an agitated patient, an agitated caregiver, agitated nursing staff, and an on-call person who doesn’t know the patient. And I think we have to think about what is the problem we’re trying to solve? Someone is having such severe hallucinations and delusions that we can’t get this drip back in, we’ve got to just dampen that down just for this evening so the junior doctor can get the drip back in so we can get some hydration to improve the renal function, and then tomorrow will be a different day, and we stop the medication and we start back.
But that needs to be a senior level decision, and really very carefully calibrated, recognising it is an off-label prescription, and it is a temporary stop-gap to solve a very complex problem, not just Haloperidol 2.5 milligrams q4th hourly or prescribed without a goal or a purpose, and then it just remains on the chart, never to be stopped. So there’s no registered medicine anywhere in the world for the treatment of delirium as a syndrome, or delirium symptoms, and that’s because there isn’t the evidence-base to support a medication for registration.
And even in the palliative care setting, because cognition is so important to people’s quality of life, having a discussion about the benefits of medications and improving people’s cognition. So it’s an important conversation in seeking the patient’s view one way or the other, and some people might say “That’s all very well, and no, I don’t want to go down that path.” But I think it’s important for us to raise the reason we think they’re important, what we’re trying to fix, and how it might help us. And people I think really are happy that you’re taking their cognition and the symptoms they’re experiencing cognitively as important as their pain and their other symptoms.
MIC CAVAZZINI: Can you talk about for acute episodes and distressing episodes for the patient and for the staff, what are the non-pharmacological ways to deescalate and engage with the patient?
GIDEON CAPLAN: People who have delirium are afraid, are concerned, do not understand what’s going on, they’re not aware really of where they are. So just talking to them, and reassuring them, and explaining what’s going on, and having, ideally if you have someone they already know, like a relative, a carer, who can explain to them where they are, what’s happening, and because of their cognitive impairment they need to be told that many times, and to be reassured many times. The things that you mentioned before about hydration and making sure they can see and hear, not overdosing them with painkillers, not underdosing them with painkillers, trying to get things not too hold, not too cold, but just – in the Goldilocks zone, yes, is what you’re aiming for.
MEERA AGAR: And you can see the difference between a very experienced nurse who has these kinds of techniques and approaches go into the room of a delirious patient and be able to get all the treatments done, the medications taken, without any disturbance at all. And then someone who hasn’t quite – grappled with those types of skills go in and say “It’s time for your medications now, you have to take it now, I don’t have time”, and escalate what was already a calm situation just by the wrong demeanour and task oriented approach. And sometimes you have to come back and try again, or say “OK, now’s not a good time, let’s just deescalate, let’s not try and persist with the thing that we think we have to do right now, because it’s just going to make the situation worse”.
MIC CAVAZZINI: What does it take, more behavioural change here in staff, what does it take to hold their attention and train them to review medications and think twice about escalating and so on?
GIDEON CAPLAN: Most residents of aged care facilities, before they went into those aged care facilities would have been seeing, certainly in this area, an average of seven or eight specialists. They go into a nursing home and they’re not seeing any specialists. So we need to have more specialist input into the care of people in aged care facilities that can advise on behavioural management, and can help to reduce and minimise the use of those medications. And there is definitely a shortage of specialists who can go into these facilities, but there’s a great need, because these are the sickest, frailest, most comorbid people in society, that’s why they’re in the nursing home.
MIC CAVAZZINI: On that transition, this is actually a question from one of the members of my editorial group, when someone’s leaving the general medicine setting, when someone’s been discharged, can you estimate their likelihood of having a repeat episode of delirium, and is there a threshold or a red flag that means you wouldn’t discharge just yet?
GIDEON CAPLAN: Well, I’d certainly say that if someone’s had one episode of delirium, the data shows they’re at high risk of having another episode of delirium. So if for example that episode of delirium was triggered by an anaesthetic by a surgical procedure, it’s important to explain to that patient and their family that if they have another anaesthetic and surgical procedure, they’ve got a higher chance of having delirium next time, and make sure that they and their family know there’s a higher risk of then getting, possibly deteriorating cognitively afterwards. And for a lot of people that may be the difference between consenting to have another procedure and not. I’m unaware of data that says how soon you’ll get that episode of delirium, because that would depend on whenever those other triggers are pulled.
MEERA AGAR: So I think there’s two things, one that keeping someone in hospital longer doesn’t necessarily reduce their risk of delirium coming back or not. Discharging someone who still is delirious may be a therapeutic manoeuvre, because they may actually improve quicker and faster in their home environment if you think about the care that they might need, and make sure that that is set up properly and that their caregiver can do that, and also they know what to do if it deteriorates again.
And I think there’s also lots of interesting instruments now being developed actually for families to be delirium screeners. The principles of the Hospital Elder Life Program are things that families can do quite intuitively. They’re designed for volunteers to do, and actually it’s really important to be both empowering families to be part of those interventions in the ward environment, but also to continue those orienting and mobility strategies at home and feel confident to do that. Because when someone’s had delirium at home, people are very cautious and say “Well, maybe we shouldn’t get them up and walking, we should just keep them wrapped up in bed and they’ll be safer”. But we actually need to build their confidence, to realise that these are part of the recovery processes, and that they’re really critical to protect the person from the risk that they now have in terms of future episodes.***
MIC CAVAZZINI: In the Australian and British guideline documents I mentioned before, it’s specified that antipsychotic medicationsshould only be considered in patients experiencing severe distress intractable by other de-escalation and reorientation techniques. These would be situations where patients risk harm to themselves or to others, or some clinical objective needs to be urgently met.Importantly, carers, and if possible patient’s themselves, should be involved in a discussion of the benefits and the side-effects of different treatments. Initially one should trial a single oral administration at the lowest possible dose just to get the patient through the critical episode. The typical antipsychotic haloperidol is the most commonly-used and its potency permits doses of 0.5mg or even lower.
The potency of a drug to treat psychotic delusions and hallucinations, comes down to its affinity for dopaminergic targets. But these same pathways are also responsible for extrapyramidal side effects like restlessness and dystonic reactions. For this reason, haloperidol must be avoided in patients with underlying Parkinson’s Disease or Dementia with Lewy Bodies. The second-generation antipsychotic risperidone has similar potency with somewhat fewer extrapyramidal effects, but it is often associated with hypotension through its adrenoreceptor antagonism.
Further down the ladder, olanzapine is 4 times less potent than risperidone and quetiapine 80 times less so. Because of the high doses needed, you get heavier sedation by histaminergic actions. And in patients with metabolic impairments especially, anti-cholinergic effects come to the foresuch as constipation, urinary retention, blurred vision and confusion. There’s very little evidence at all for benefit of quetiapine on the florid symptoms of delirium. From Claude’s charts, it appears that his clinicians were just trying to calm his extreme agitation. But the fog and the peripheral side-effects he described can greatly impact on quality of life too. Meera Agar says that patients at the end of life would often rather preserve mental alertness than have total symptom suppression. If you’re not able have this discussion about trade-offs before administering a psychotropic, it’s ethically incumbent to do so once the patient becomes lucid again.
In some jurisdictions it is also a legal requirement to obtain substitute consent from a guardian before using medications to ‘control behaviour’ of a patient with dementia.Risperidone is listed on the PBS for treating aggression associated with Alzheimer’s Disease, but overuse of chemical restraints in aged care has been one of the confronting findings of Australia’s Royal Commission into Aged Care Quality and Safety. In audits of patient records from Sydney nursing homes, it’s been shown that substitute consent for prescribing antipsychotics is sought for only a small fraction of dementia cases. And scripts often continue for over two years on average compared to the three month limit indicated. On top of all the side effects I’ve already described above, prolonged antipsychotic use is associated with cardiac arrhythmia and sudden cardiac death.
The guardianship legislation I’ve described is not directly relevant to bouts of delirium, where the principles of necessity and safety would hold up, and it’s expected that the patient will ultimately regain capacity. But it still makes you think, and bear in mind that some 30% of older patients who develop delirium during acute general admissions will have an underlying cognitive impairment. Another factor to consider in severely agitated patients is whether oral administration of medication is even possible, in which case haloperidol and olanzapine can be given by intramuscular injection. And as we’ve said, comorbidities really make a difference to drug selection. For example, quetiapine might be a tolerable alternative to more potent drugs in patients with underlying Lewy Body Dementia, but it’s been associated with worse cognitive decline in those with Alzheimer’s Disease.
According to the UK guidelines from the National Institute of Clinical Excellencetreatment should be strictly titrated against presence of symptoms and administration should not continue for more than a week. If a patient is discharged with a script for a antipsychotic carers and community doctors must be given instructions for tapering off. Otherwise, there is a demonstrated risk that these prescriptions initiated in hospital are then continued when patients are received into nursing homes. I’ll leave the final word to Adam Kwok, who has been advocating for a better education around delirium for the public and for clinical staff.
ADAM KWOK: And I guess the thing that I learned in a sense then, and since I’ve become a little bit more outspoken about our experience, and what’s more shocking is how common it is, and in fact I did a bit of research and looked up on the internet to see whether I can find much information on delirium—very little. You know I think that’s part of the problem.
And in terms of the treatment at three different hospitals, and in terms of his response to treatment, it couldn’t have been more different. And so it just appears to me that there’s no standard protocols for delirium. And so it comes down to the experience of the staff who were on duty at the time. And with the first experience, I certainly had never seen delirium or experienced it before, and that was quite frightening, because just the fact that I didn’t understand what’s happening.***
MIC CAVAZZINI: Many thanks to Adam Kwok for sharing his and Claude’s medical journey so openly. Thanks also to Meera Agar and Gideon Caplan for all their time and expertise. Professor Agar has written a comprehensive chapter on Delirium for the Oxford Textbook in Palliative Medicine. I’ve linked to this at racp.edu.au/podcast, along with the some of the most useful guidelines from the UK and the Australian Clinical Care Standards. At our website you’ll also find links to some great simulation videos on delirium management from the Western Australia Clinical Training Network and to lectures in our College Learning Series by geriatricians Sean Maher and Michael Murray. If you prefer listening, I’ve posted an episode of the GeriPal podcast featuring Sharon Inouye, a doyen in this field who was kind enough to answer a couple of my emails.
I also want to thank all the members of the podcast editorial group who provided advice on this story. They’re named one by one at the website, where you can also make your contribution to our Comments section. Please tell your friends and colleagues to subscribe to Pomegranate Health- if they don’t have the latest podcasting app they can sign up for email alerts instead. I’m Mic Cavazzini. I hope to hear from you.