Delirium can be described as “an acute brain dysfunction and that’s normally, typically, in response to a pathophysiological trigger, for example, exposure to a medicine or an acute infection or a change in a chronic condition”, explains Dr McKenzie. A diagnosis of delirium is important because it is the leading cause of cognitive decline in the acute care setting.

Risk factors for delirium include old age, severe infections, ischaemic heart disease, genetic predisposition and the anticholinergic burden of drug therapy.  “In the simplest terms, the higher the anticholinergic burden, the greater the risk of delirium, constipation, confusion, falls and, actually, if you expose yourself to these drugs for long periods of time you can actually develop dementia”, says Dr McKenzie.  The most well-known drugs are oxybutynin and solifenacin which are prescribed for management of urinary incontinence. “Polypharmacy in the elderly increases massively this anti-cholinergic burden”, she says.

The only group of drugs that has been shown to have any benefit is the alpha-2 agonists, clonidine and dexmedetomidine. Non-pharmacological treatments including early mobilisation, cognitive stimulation and re-establishment of the sleep-wake cycle are helpful.

Delirium is a major feature in severe covid-19 infection and about 25% of those affected will go on to develop cognitive decline.

One avenue of active research is into the use of intravenous thiamine for delirium.

Pharmacists in all sectors need to be aware of delirium because they all have something to contribute to the management and prevention of delirium. In ICU, “the more sedative an opioid we give to the patient the greater the risk of delirium later – so we should be there at the bedside every day ensuring that the doses are right for that patient and they are regularly reviewed”, says Dr McKenzie. In primary care it is important for pharmacists to monitor drug therapy to ensure that the anticholinergic burden does not escalate.

Pharmaceutical expertise is valuable in the intensive care setting and Dr McKenzie’s advice to young pharmacists thinking about a career in critical care pharmacy is “Don’t hesitate!”

Dr Cathrine A McKenzie, BsC PhD FRPharmS is Clinical Academic Research and Reader in Critical Care Therapeutics, Kings Health Partners, and Senior Pharmacist in Critical Care, University Hospital Southampton.  She is also Editor-in-chief,  Critical Illness www.medicinescomplete.com.

Read and watch the full series on our website or on YouTube.

Pharmacists in the intensive care unit (ICU) should be aware that when ventilated patients are given sedatives and opioids “there is reasonable evidence that the more sedative an opioid we give to the patient the greater the risk of delirium later – so we should be there at the bedside every day ensuring that the doses are right for that patient and they are regularly reviewed. … It’s even more complicated in ICU, of course, as many of these patients have got multiple organ failure – their kidneys don’t work, their livers don’t work properly and, of course, that’s how we metabolize and eliminate drugs. So, the pharmacist should be there understanding the drug, understanding the sedative, and understanding the antimicrobial, [as well] because very high doses of them can cause delirium”, says Dr McKenzie. They should also be questioning therapy that is of limited benefit, for example, long courses of antipsychotics.

As patients begin to recover,  pharmacists should be reviewing their prescriptions and ensuring therapy that is no longer necessary is not continued long-term.  “As well as all that, which is our professional role, we should also be talking to our patients, even when they’re acutely unwell. … Remember, this orientation in time and place is very important. Of course, if someone’s on a very high concentration of oxygen and they’re deeply sedated, they’re too unwell but as they’re coming round [and] as they’re being rehabilitated, I always encourage my pharmacy colleagues to introduce themselves to the patients. This stimulation is actually quite important”, she explains.

When patients return to medical wards the pharmacist’s task is again “about medicines optimisation – reducing and stopping therapies that were started in the ICU that would be deliriogenic in the longer term”, she says. Other key tasks include orientating patients in time and place and reducing their anticholinergic burden. “This might be a good time for the pharmacist to look at the patient’s long-term medicines and perhaps talk to the patient about those that are likely to have an increased anticholinergic burden in the longer term and change or optimise their therapy”.

At the time of discharge, it is important to ensure that treatment is appropriate. For example, after major surgery opioids may be required for pain control but “that doesn’t mean [the patient] should go home on a long-term opioid, which increases the risk of delirium”, says Dr McKenzie.

In the community setting “there’s a huge role”. In this context, the proposed POM to P switch for oxybutynin is causing some concern because of the high anti-cholinergic burden associated with the drug. “I think pharmacists should be aware of the risks that this drug poses in terms of triggering dementia. As I said, long-term exposure certainly increasing the risk of delirium. So, it’s about properly counselling the patient and in a very elderly patient, perhaps … recommending another therapy. …  I’d like to say, encourage them to [take] thiamine but of course that’s not evidence-based medicine yet because we don’t really have the evidence, she says. “Actually, if we know the patient is alcohol-dependent, checking that they are on long-term thiamine therapy will reduce their delirium- but that’s alcohol-associated delirium”, she adds

Critical care pharmacy

Dr McKenzie’s advice to young pharmacists thinking about a career in critical care pharmacy is “Don’t hesitate! It’s a great speciality to go into”.  One of the attractions for her has been the strong focus on basic pharmacology and pharmacokinetics. “We take the drugs back to first principles a lot, you know, so we have to understand the drug properties, its pharmacokinetic properties and how it’s dosed within that patient – and we do that on a daily basis. So, if you’re passionate about keeping that side of your pharmacokinetic brain alive, it’s the speciality for you. And, actually, we’re a real multi-disciplinary team – we work very well together. I think it’s a huge area for pharmacists [with] a large number of consultant pharmacists – a number of us have PhDs – lots of opportunities to research. So, don’t hesitate!”

Dr Cathrine A McKenzie, BsC PhD FRPharmS is Clinical Academic Research and Reader in Critical Care Therapeutics, Kings Health Partners, and Senior Pharmacist in Critical Care, University Hospital Southampton.  She is also Editor-in-chief,  Critical Illness www.medicinescomplete.com.

Read and watch the full series on our website or on YouTube.

“When we first started to understand about delirium, we thought it was a neurotransmitter problem so we searched among our dopamine antagonist agents which, of course, are the antipsychotics, and they are used so very commonly in the acute sector to treat delirium. Sadly, the evidence for these therapies is lacking for delirium …..I  mean the syndrome of delirium which causes the cognitive decline”, says Dr McKenzie. For patients who have delirium who become very agitated, antipsychotics including haloperidol, quetiapine and olanzapine will have some effect in reducing the agitation but they will not affect the delirium syndrome. In addition, benzodiazepines can be helpful for acute agitation but long-term infusions are believed to be harmful and are avoided. Opioids can also be a cause of delirium, she adds.

“The only group of drugs that have been shown to have any evidence of benefit, I guess, are the alpha-2 agonists. The two drugs that we know in the intensive care unit (ICU) …. are clonidine – of course, it was originally anti-hypertensive, now used in chronic pain and agitation of delirium in ICU – and dexmedetomidine. There’s actually quite reasonable evidence that dexmedetomidine will treat and prevent delirium. What is disappointing for us in ICU is that that evidence was really assessed in patients that were not severely, severely unwell, if that makes sense. It was in patients who were quite severely unwell and they used the dexmedetomidine to prevent them getting worse”, explains Dr McKenzie. The evidence for clonidine is weaker and she is now involved in a study called ‘A2B’ that is comparing dexmedetomidine versus clonidine versus standard care and one of the secondary outcomes is delirium prevention.

She notes that it is “the vulnerable brain”, that is particularly at risk for delirium. “Although, I have to say, we do get delirium in children as well and that’s probably because they’re so unwell. Whether we get the same cognitive decline – it’s yet to be established”, she adds.

There are a number of non-pharmacological therapies which have been shown to reduce delirium although none has been shown to prevent the subsequent cognitive decline. Early mobilisation is one measure that helps and this is why patients in ICU [and] critical care who have undergone, for example, hip replacements are mobilised as early as possible.  Cognitive stimulation is also helpful. This can involve talking to the patients, interaction with relatives, orientation in time and place and, most-importantly, re-establishment of the sleep-wake cycle. “In fact, one of the things in ICU [that] we’re not particularly good at is keeping our patients in a cycle because when they’re acutely unwell we give them infusions of sedatives and opioids and that completely destroys it, of course. So, when they wake up, they’re completely disorientated and when we get them back into a normal regime the delirium prevalence reduces”, says Dr McKenzie.

In intensive care units it is difficult to maintain the normal daytime-night-time rhythm. When patients are acutely unwell, they are not treated in a single room because observations have to be undertaken every hour. “Darkening the room does help.  Interestingly ,…. there’s been a ton of studies looking at melatonin in delirium because instinctively you think it would work but as far as I’m aware there’s no evidence of any benefit”, she notes.

Delirium with covid-19

Delirium is “a huge feature in covid-19 and I believe in older patients who develop covid one of the main symptoms is delirium. What we have seen with covid 19 is a prolonged and severe delirium. Now, that’s probably related to the course of the virus. …..  I accept the most recent omicron [variant] is much milder but severe covid was a long illness so we think there are effects of the virus on the brain”, she says. These may be due to the effects of microthrombi in the brain or the effects of neural inflammation that goes alongside. “The latest literature, I believe, is suggesting those with severe covid – there’s about 25 percent of them who have later cognitive decline which is dreadfully sad … if you’re a young patient. …. I’m not saying patients will never recover, you know, there is some evidence that patients will recover but there are accountants who can’t add up, you know, mathematicians who can’t add, people who can’t go back to work, people who you know no longer pursue a full and independent life. ….  I think part of this brain fog, you know, which is a typical sign of long covid …..  is triggered by the acute delirium the patients have had when the disease is worst and this triggers, we think, an inflammatory process in the brain which takes some time to resolve”, explains Dr McKenzie

Research into new treatments

Dr McKenzie is leading a research group that is exploring the use of intravenous (IV) thiamine (vitamin B1) supplementation in delirium. She explains: “Thiamine diphosphate is the active form of thiamine and it’s an essential co-factor in the number of enzyme systems in the brain. … Our most recent hypothesis is that delirium is triggered by an abnormal glucose metabolism or under-glucose- metabolism and we need thiamine in a number of these enzyme systems, including alpha ketoglutarate and transketolase. We think that we have reasonable evidence to suggest that flooding the brain with thiamine in delirium may reduce its prevalence in ICU. What’s very encouraging is that thiamine is actually very, very safe. In fact, it’s safer than most of the other drugs, as you know, and of course it’s been used in the NHS – many people will remember it’s Pabrinex.  … We don’t convert thiamine to its active form in alcoholism so of course it’s one of our main treatments of Wernicke’s {encephalopathy], so we know that it’s safe. We think that it’s effective; we’re just hoping very much to get funding to undertake a small study to prove that it gets into the brain in delirium and reduces the brain network disintegration, which is essentially delirium, and then finally undertake our large site randomized control study to assess the effects of IV thiamine versus placebo in delirium.”

Dr Cathrine A McKenzie, BsC PhD FRPharmS is Clinical Academic Research and Reader in Critical Care Therapeutics, Kings Health Partners, and Senior Pharmacist in Critical Care, University Hospital Southampton.  She is also Editor-in-chief,  Critical Illness www.medicinescomplete.com.

Read and watch the full series on our website or on YouTube.

Older age is probably the biggest risk factor for delirium. This could be because the blood brain barrier deteriorates with age and noxious substances are more likely to penetrate the brain. “Severe infection, sepsis and septic shock can often present with delirium. There’s a bit of a confusion in the language in that some of the sepsis language calls it encephalopathy but actually there’s a lot of overlap between both”, says Dr McKenzie.  Alcohol dependency can also be a risk factor. “Patients who are alcohol-dependent come into the ICU and develop delirium are much more challenging to treat”, she says.  Another factor can be a genetic predisposition to dementia. Such patients may be “on the pathway to developing dementia” and, for example, already be attending a memory clinic.  Ischaemic heart disease can also be a risk factor. “Delirium is very common on cardiothoracic wards, in cardiac areas and …. we think that’s because part of the challenge in delirium is atherosclerosis in our great vessels and our brain and associated neural inflammation”, explains Dr McKenzie. Intensive care clinicians believe that statins could be helpful here. “we think they work but the evidence is still lacking”, she adds.

In recent years there has been a growing understanding of the role of the total “anticholinergic burden” in the development of delirium. “In the simplest terms, the higher the anticholinergic burden the greater the risk of delirium, constipation, confusion, falls and, actually, if you expose yourself to these drugs for long periods of time you can actually develop dementia”, says Dr McKenzie.  The most well-known drugs are oxybutynin and solifenacin which prescribed for management of urinary incontinence. A GP colleague recently told Dr McKenzie that, in practice, it is difficult reduce the use of these drugs because patients who are taking diuretics refuse to stop oxybutynin and solifenacin because control of continence is more important for them. Oxybutynin and solifenacin both have pronounced anticholinergic effects but “what will often happen is patients that are on a number of medicines that have a low risk, but added together is a high risk – and that’s why polypharmacy in the elderly increases massively this anti-cholinergic burden”, she says.  Reducing the anticholinergic burden reduces the risk of delirium.

A high anticholinergic burden can become apparent in the acute setting as falls or constipation. Dr McKenzie says, “I work partly on the neuro-ICU and I’ve seen some patients recently coming in with subdural hematomas which are … as a consequence of quite drastic falls and they’ve been on three or four drugs with this high anticholinergic burden. This is more of a risk for our older patients and we think this is again because of the blood-brain barrier being less intact so the risk is higher. …..Classic drugs of course are like those like Nytol (diphenhydramine) …  they have a massive anti-cholinergic burden. So, they’re great in the short term – they help us sleep – but in the longer term in the elderly patients they are a risk”.

Dr McKenzie emphasises that often the drugs that contribute to the total anticholinergic burden are not being used for their anticholinergic effects, as such, but have these effects as part of their pharmacological action. She explains, “These anti-cholinergic effects are not immediately noticeable. A very recent one I noticed was olanzapine, actually, and in fact people …. who work in ICU will recognise that actually we use … olanzapine to treat delirium. It actually has a reasonable anticholinergic burden so there’s not much evidence that it actually helps delirium but there’s even more evidence showing now that it …may trigger it”.

Dr Mckenzie expects that there will be increasing amounts of information about the anticholinergic burden and it will be important to keep patients informed of the risk.  Another group of drugs that gives cause for concern is compound analgesics, such as cocodamol, with high amounts of codeine.  Used on its own in elderly patients it is likely to be tolerable but when added to oxybutynin or promethazine “that’s a very high anticholinergic burden and that will massively increase the risk of confusion, delirium and falls”, she says.

Dr Cathrine A McKenzie, BsC PhD FRPharmS is Clinical Academic Research and Reader in Critical Care Therapeutics, Kings Health Partners, and Senior Pharmacist in Critical Care, University Hospital Southampton.  She is also Editor-in-chief,  Critical Illness www.medicinescomplete.com.

Read and watch the full series on our website or on YouTube.

As a clinical academic pharmacist Dr McKenzie combines clinical practice in critical care with an academic role in which she both conducts her own research and supports other pharmacy professionals undertaking research.  She has worked for more than 25 years in critical care at the University Hospital of Southampton. Her academic work is based at King’s Health Partners.

Delirium can be described as “an acute brain dysfunction and that’s normally, typically, in response to a pathophysiological trigger, for example, exposure to a medicine or an acute infection or a change in a chronic condition. The key symptoms of delirium are confusion but this presents as inattention, …. so, you might be half way through a sentence and you can’t get to the end – and actually a lot of the screening tools capture this symptom – as well as disorganization in thinking. So we ask patients things like, ”Are there fish in the sea?”,  “Is one pound more than two pounds?”  and you’ll often get the answers confused. And it’s a change in one’s cognitive function from baseline”, explains Dr McKenzie.  “It’s very distressing for our patients, for their relatives and for those that are caring for them”, she adds.

A diagnosis of delirium is important because it is the leading cause of cognitive decline in the acute care setting. Dr Mc Kenzie says, “That’s not just in critical care that’s in acute care. So, a patient that’s in delirium ……. they have a chance of about a third of developing some kind of cognitive decline after their episode [of delirium].  The longer they’re in delirium, the more severe it is, the worse the cognitive decline will be and elderly patients with delirium have a much lower chance of leaving hospital and returning to their own home and leading full independent lives. In addition, it increases our chance of dying, it increases our hospital and ICU length of stay and, as I said, lastly, it’s terrifying for patients, it’s very distressing for the relatives and it’s hugely challenging for those caring for them”.

Delirium is probably triggered by an underlying problem and could be something as simple as advancing age. “Elderly patients, for example, who get urine infections will often not present with a [raised] temperature, they present with delirium. It is not the same as dementia but it is more common in dementia and may be an indication that patient may develop dementia……There’s a lot of difference between having a little bit of cognitive decline, you know, having a little bit of failure memory or remembering things and going [down] the path to having …. severe dementia. …An episode of delirium will hasten that decline markedly”, she explains

In patients in intensive care who are severely unwell, the prevalence of delirium can be as high as 70 percent and even higher amongst those who are mechanically ventilated.  Moreover, when asked about research priorities stakeholders ranked agitation and delirium at number three. “So, it’s a huge problem for us and a research priority for us”, says Dr McKenzie. “That’s a huge challenge and I actually know it has a huge impact, particularly on our nursing colleagues who are caring for these patients, who find care of these patients challenging and seeing the patients in great distress can be …. hugely challenging as well”, she adds.

Dr Cathrine A McKenzie, BsC PhD FRPharmS is Clinical Academic Research and Reader in Critical Care Therapeutics, Kings Health Partners, and Senior Pharmacist in Critical Care, University Hospital Southampton.  She is also Editor-in-chief,  Critical Illness www.medicinescomplete.com.

Read and watch the full series on our website or on YouTube.