Delirium in Critical Illness
Delirium among the critically ill has been discussed in several SAQs:
- Question 12 from the second paper of 2016
- Question 6 from the second paper of 2013
- Question 29 from the second paper of 2009
The more recent question was more general and did not expect any information regarding the prevalence or prognostic significance of delirium. Delirium is defined as a disturbance of consciousness, characterised by inattention, which develops acutely, and fluctuates in severity; there are specific investigations, acute management issues and pharmacological or nonpharmacological solutions. To prepare oneself for such SAQs as listed above, the savvy candidate will choose a relatively recent review article (let us say, Arumugam et al from 2017) to take advantage of somebody elses's work in trawling through the literature (the abovementioned authors' search strategy yielded 8919 articles).
An exam-focused approach to delirium:
A systematic approach to a delirium question would resemble the following:
Urgently exclude and manage any lifethreatening aetiologies of delirium:
A) - Look for airway compromise due to decreased level of consciousness
B) - Assess for hypoxia and hypercapnea
C) - Assess for hypotension (thus cortical hypoperfusion) or hypertension (thus, hypertensive encephalopathy)
D) - Exclude hypoglycaemia and intoxication or poisoning; investigate for focal intracranial causes of delirium, such as intracranial haemorrhage or space-occupying lesion. Think about non-convulsive status epilepticus as the cause of delirium. Also consider withdrawal from alcohol and other drugs.
E) - Evaluate electrolytes, looking for hyponatremia
F) - Assess renal function, looking for uremia and dehydration
G) - Assess hepatic function, suspecting hepatic encephalopathy. Don't forget Wernicke's.
H) - Assess bone marrow function - cytopenia may be a clue to a space-occupying metastatic lesion, whereas blood film findings such as macrocytosis may suggest a chronic nutritional deficiency associated with alcoholism or IV drug abuse.
I) - Assess temperature, inflammatory markers and features of sepsis, ranging from UTI to septic shock (thinking about septic encephalopathy). Consider neurosyphilis and think about meningitis or encephalitis.
Investigation of delirium:
Stemming from the aforementioned differentials,
- Blood film
- Inflammatory markers
- CT brain
- Lumbar puncture
Management of delirium
- Good analgesia
- Clear and firm communication with the patient
- Frequent re-orientation
- Family presence
- Low-noise environment
- Restoration of hearing aids and spectacles
- Avoidance of sleep disturbance, promotion of normal sleep–wake cycle.
- Avoidance of physical restraints
- Early removal of IV lines and IDC
- Adequate hydration
- Adequate (oral) nutrition
- Use of thiamine
- Atypical antipsychotics
- Classical antipsychotics
- Benzodiazepines (if withdrawing from alcohol or benzodiazepines)
Definition of delirium
This is how the DSM V puts it:
The DSM -V diagnostic criteria for delirium:
Disturbance in attention (ie, reduced ability to direct, focus, sustain, and shift attention) and awareness.
Change in cognition (eg, memory deficit, disorientation, language disturbance, perceptual disturbance) that is not better accounted for by a preexisting, established, or evolving dementia.
The disturbance develops over a short period (usually hours to days) and tends to fluctuate during the course of the day.
There is evidence from the history, physical examination, or laboratory findings that the disturbance is caused by a direct physiologic consequence of a general medical condition, an intoxicating substance, medication use, or more than one cause.
Classification of delirium
Delirium comes in three flavours: hypoactive, hyperactive, and mixed. The hyperactive patients we all know and love. They are the ones who can be seen hanging half way out of their bed, fiddling with their femoral line insertion site with their scrotum on display. They claw at the nurses, use foul language, discuss inappropriate things with invisible people, and otherwise demand our attention. They actually do rather well - this vigorous surplus of activity is good exercise. The perpetual fidgety self-repositioning is protective against pressure sores, and the constant muscular activity prepares them well for subsequent efforts at physiotherapy and rehabilitation (once they find their marbles and begin to cooperate).
In contrast, the hypoactively delirious patient merely sits there, looking at you with those vacant eyes. They have no idea where they are, and cannot recall events from one minute to the next, but their profound apathy allows them to camouflage their delirium. Unless somebody performs one of those well-validated CAM-ICU examinations on them, many will be mistaken for the something else- maybe even for normal calm people. This, perhaps, is why these delirium screening tools are so effective at recognising the delirious patients, and why without their use delirium frequently goes unrecognised.
Most delirious patients exhibit features of hyperactivity at least at one stage or another, and so none fall very precisely into either of these definitions, which is confusing but I suppose this is in keeping with the topic. Of the overall spectrum of delirious patients, about half will oscillate between frenzy and apathy.
Prevalence of delirium in the ICU
A prospective observational cohort study from the Netherlands have reported some distinctions among ICU patients, with regards to who is likely to "go off" and who will retain their wits.
Neurosurgical and cardiothoracic patients had the lowest incidence(~10%). This is surprising, considering one group spent their theatre time cooled down to 15° and bypass-pumped, whereas the other group had their heads drilled open. However, one might reflect on the fact that most of this patient population were probably elective outpatients, and thus were built out of more robust protoplasm.
Neurological patients had the highest incidence (~64%). The article does not mention the sort of neurological problems which might have brought these people to hospital. Was it Guillain-Barre, status epilepticus, or what? It would be interesting to know.
Prognostic significance of delirium
What's the harm in being delirious? Seems harmless, one might say. Its just merciful nature's way of preventing you from directly confronting the horror of your intensive care admission. So, why interfere with it? Why go out of our way to identify the delirious patients? Well, turns out the state of brain failure is not entirely benign. And this seems to be completely divorced from all the untoward attention these people earn from their doctors, what with all those extra boluses of haloperidol.
The 2004 Ely prospective cohort study gets brought out whenever anybody talks about the prognostic significance of delirium in the ICU. There are many others. In summary, their findings were as follows:
- Mortality at 6 months: increases × 3.2
- Length of hospital stay doubles
- Every additional day of delirium increases the hazard of death at 1 year by about 10%.
- Increased risk of cognitive impairment in the long term (in ~ 70%)
Delirium increases the duration of ICU stay
And not in a trivial way. A good (and widely quoted) prospective study by Ouimet(2007) measured a 5-6 day difference in the duration of stay - from an average of 4.4 days to a whopping 11.5 days. This makes some sense- a delirious patient scores more sedation, ends up extubated later, and refuses to cooperate with physiotherapists, making their respiratory rehabilitation a difficult task. Not to mention all the nutrition lost due to pulled out NG tubes. However, one must recall that a high severity of illness is thought to be a risk factor for both delirium and for long ICU stay; it may well be that this difference in the length of stay is to some extent exaggerated.
Delirium increases ICU mortality
And in-hospital mortality as well. The numbers from the same study (if we are to trust them) were 10.3% mortality for the cognitively intact patients, and 19.7% for the delirious patients. This is not to imply causation - being delirious on its own is not killing these patients. One must consider the idea that illnesses of greater severity generate a higher death toll as well as a higher incidence of delirium. Even when mortality data was adjusted to illness severity, Ouimet's group still found an increased risk; however, other investigators have subsequently failed to find a conclusive association between delirium and mortality, once severity of illness was adjusted for.
Delirium is a predictor of long-term cognitive impairment
Even after adjusting for pre-existing cognitive performance, education level, severe sepsis and severity of illness, Girard et al found that people who were delirious in the ICU continue being slightly fuddled in their post-ICU life, even many months after their discharge. More interestingly, the duration of delirium seems to have a dose-effect relationship: for every day spent in its grip, one suffers a half-standard-deviation decrease in cognitive performance scores. 71-79% of ICU delirium survivors had some degree of cognitive impairment event at 1 year of follow up. This has subsequently been confirmed by other investigators. In fact critical illness in general seems to lead to cognitive decline - an earlier literature review from 2006 found roughly similar rates (25-78%) among survivors of medical or surgical intensive care.
Risk factors for delirium in the ICU
Four significant risk factors for delirium have been identified:
- Pre-existing dementia
- History of hypertension
- History of alcoholism
- High severity of illness at admission
In addition to these, several other associated factors have been discussed in the literature:
- Benzodiazepine use ... when they are used to induce coma
- Opiate use ... again, it seems this is only an issue if the opiates are used with the aim of producing or supporting unconsciousness.
Significant risk factors:
Preventable risk factors
Uncontrollable risk factors
Modifiable risk factors
On top of this, our beloved Oh's Manual lists even more risk factors. Some of them seem to have been lifted out of a recent systematic review, which within its cavernous depths contains a beautiful chart of risk factor vs. odds ratio, demonstrating which of these risk factors contribute the most. Weirdly, age seems to be the least important. High serum amylase for some reason increased the odds the most - OR was around 80.
Together, Oh's table and this review can be combined into one master table:
On the basis of this abovementioned review van Boogard and friends have developed and validated a screening tool (PRE-DELIRIC).This tool collects information about 10 risk factors (such as APACHE-II score, age, morphine dose, urea concentration etc.) and applies a coefficient to each (eg. 0.03 × urea concentration), arriving at a number which - at predicting delirium before it occurred - performed significantly better than the clinical judgment of doctors and nurses. The model has been refined by means of a more recent (2014) prospective cohort across six countries, and looks like a good method for identifying patients in whom early preventative intervention might be of benefit. Which brings one to ask: what sort of preventative strategies could one deploy to address such a multitude of heterogeneous risk factors?
Prevention of delirium
Early mobilisation is the only strongly supported preventative measure.
The Clinical Practice Guidelines statement of 2013 makes only one recommendation: early mobilisation. The rest of their recommendations start with the words "we provide no recommendation". These non-recommendations refer to the use of prophylactic antipsychotics and dexmedetomidine.
This call for early mobilisation seems to be derived from a 2009 trial from the Lancet,
Those people had physiotherapists attempt to mobilise mechanically ventilated patients, as soon as practical in the earliest stages of their ICU stay. However, it must be mentioned that this study only enrolled patients who were already highly functional and independent. Its hard to say what would happen if this practice were applied to the usual ICU protoplasm - the chronic alcoholics, patients with dementia, liver failure, end-stage renal disease, severe sepsis, and so forth. The median APACH-II score was only 19.5, suggesting that these patients were of HDU quality. And of course this trial was totally unblinded, leaving it open to criticism regarding bias - especially regarding things like weaning sedation and ventilation. Oh well. These caveats did not stop the The American College of Critical Care Medicine from issuing a Class +1B recommendation for this practice- by their definition, a strong recommendation based on moderate quality evidence.
Ancillary measures to prevent delirium
Oh's Manual makes several further recommendations, as a part of a "multicomponent intervention" to prevent delirium. These may not be as well supported as the "early mobility" recommendation - for one, the study I have linked to is not ICU-specific, but conducted in a population of elderly ward patients. Still, from this population much of our delirium-associated workload is generated.
So, these are further preventative recommendations.
- Good analgesia
- Clear and firm communication with the patient
- Frequently re-orientate the patient, including date, time and location.
- Involve the relatives to calm the patient
- Keep noise to a minimum
- Give them back their hearing aids and spectacles
- Avoid sleep disturbance, promote normal sleep–wake cycle.
- Avoid physical restraints
- Remove lines and IDCs as soon as they become redundant
- Sedate mildly, aiming for a RASS from 0 to -1
- Consider daily awakening trials
Daily sedation interruption and delirium
There is an argument that "sedation holidays" may prevent delirium. Some believe that prolonged deep sedation has some sort of a mysterious brain-scrambling effect, and that somehow brief episodes of sedative cessation prevent this effect. Certainly Girard's 2008 study had demonstrated a clear improvement (of mortality, mind you, rather than delirium, but I suppose one must have their priorities).
Significantly more patients in this "sedation holiday" group self extubated, which actually is an argument for an increase of delirium, given that coherent and cooperative patients usually have sufficient good judgment to leave their life support machinery unmolested.
The difference was considerable: 16 patients versus 6 in the constantly sedated group. Sure, most of the patients who self-extubated also remained extubated, but no mention is made of delirium as an outcome. Thankfully, a subsequent study of sedation interruption (2012) aimed to answer this question. Incidence of delirium was unaffected; the only change was an increase in nursing workload (wrestling with the crazed patient, one might suppose). In keeping with this notion, the rates of self-extubation in this study were not affected by sedation interruption - again, perhaps because the nurses were performing in the role of physical restraints.
Causes of delirium
In the majority of situations, when confronted with the question "what is causing this specific patient to be delirious", one comes - after an exhaustive search - the the conclusion that it is a "multifactorial" disorder. Rightly so. Very infrequently can any single thing be blamed for the state of confusion. Typically, the ICU patient has a hundred things wrong with them, and of that hundred at least fifty are affecting the way their brain works. These issues have prompted the more pragmatic investigators to question whether delirium is a "satisfactory construct", given the breadth of behavioral abnormalities and biological features which are not included in the standard definition. However, the ICU exam candidates are forever exposed to questions which ask them to generate several reasons for a given episode of delirium. In this case, it is better to view these "causes" more as risk factors and conditions which are commonly associated with delirium.
ICU delirium as a unique aetiology
This is an altered level of consciousness attributed purely to the effects of being in the horrific environment of the intensive care unit. It tends to develop after 5-7 days of admission. Sharp objects are constantly poking you, your bed is uncomfortable, the calf compressors keep waking you up, the nurses keep waking you up and asking you stupid questions, the machines keep alarming, the lights seem to be perpetually on, the environment is hostile and monotonous and they keep filling you with psychoactive drugs and you just can't sleep - who can blame you for becoming slightly deranged? Certainly, 20-80% of ICU patients have some fluctuating disturbance of consciousness .
Diagnosis of ICU delirium
This is a diagnosis of exclusion. There are plenty of other reasons for encephalopathy in the ICU, and one must convince oneself that none of these are playing a role.
Detection of delirium
The Clinical Practice Guidelines statement of 2013 recommends that everyone in ICU should be screened with CAM-ICU or the ICDSC. In general, it seems sensible. The guidelines panel also thought it was possible to implement this without a massive demand on manpower resources.
Management of delirium in the ICU
Well, we generally like to infuse drugs into these people. Seems like a good idea. Intensivists as a broad generalisation are fond of maximally intrusive therapy; so, when one's cognitive state becomes grossly counterproductive, we deploy molecules which invade the brain tissue and make crude adjustments to the abovementioned cognitive state.
Again, we have the Clinical Practice Guidelines statement to refer to.
The following things work to decrease the duration of delirium:
- Atypical antipsychotics (but this is based on very weak evidence)
- Dexmedetomidine (when compared to benzodiazepines)
The following things don't work:
No mention is made of humble haloperidol, and yet it seems to have been the most frequently used drug in the delirious population. How did this come to be? Some of those whom I have asked have replied that it is available as an intravenous formulation, and has fever anticholinergic side effects than chlorpromazine. This, perhaps, is not a good enough reason to rely upon it as the sole agent to control the misbehaving elderly.
Haloperidol had enjoyed a period of popularity when studies like Milbrandt et al (2004) were being published, (that one in particular found a decrease in in-hospital mortality associated with the routine use of haloperidol). Weirdly, the investigators digressed from the delirium-controlling context of haloperidol use, and instead held forth extensively on its "unintended immunomodulation" - turns out, haloperidol has some sort of poorly understood anti-inflammatory effect. This is another case of a drug being used because its has a (maybe) beneficial side-effect, which somehow justifies its use despite its otherwise poor performance in its primary role.
So how poor is it, really? A 2013 study of "prophylactic" haloperidol in ICU patients found that at a dose of 2.5mg tds haloperidol was as effective as the placebo, in terms of delirium incidence. However, unlike the saline placebo, haloperidol has all sort of nasty side effects. Perhaps one could argue that if one were going to keep prescribing ineffective drugs, one should at least ensure that they are safe and free of side effects.
Indeed, olanzapine is equally effective in this setting, but with fewer extrapyramidal side effects. It is probably just as easy to slip in a sublingual tablet as it is to break an ampoule. Thus, in this era, we find ourselves using atypical antipsychotics, not because the evidence for their efficacy is particularly strong, but because they are safer than the alternative.
Choice of atypical antipsychotics for the management of delirium
It is difficult to discriminate between antipsychotic drugs, and after some experience with them one comes to the conclusion that atypical antipsychotics are all equipotent when it comes to the management of delirium. Some evidence exists, but not enough to set one drug on a pedestal above the others.
All we can say is this:
- Atypical and typical agents have equivalent efficacy
- Olanzapine is better (safer) than haloperidol
- Quetiapine plus haloperidol is better (more effective) than haloperidol alone
- Risperidone is as good as olanzapine
- Quetiapine and risperidone are better for the delirious dementia patient; in the over-75 age group response to olanzapine seems to be poorer (at least in Korea)