PsychoTropical Research - Dr Ken Gillman, Serotonin Syndrome, Mirtazapine, Dual Action Drugs.Brain failure - Delirium.

PsychoTropicalResearch, serotonin and serotonin syndrome research.

Brain failure - Delirium

Brain failure - Delirium

Date Created: 06/03/1999   Last Modified: 03/10/2002   Last Checked: 03/01/2003

Delirium is a major health care cost, medico-legal problem, patient care and medical audit issue.

Delirium is a common problem with aged hospital patients where it may be iatrogenic. It is frequently caused / precipitated by anti-muscarinic drugs, so it is advantageous to be aware of drugs that have anti-muscarinic properties. If such drugs are given to susceptible patients serious iatrogenic toxic confusional states (delirium) will result. These may be avoided by knowing which drugs have anti-muscarinic effects and not using them in at risk patients, or ceasing them if delirium is manifest.

Patients who may be particularly susceptible include:- past head injury, organic brain disease, the aged especially those with prodromal dementia, Parkinson’s, and those already on other agents with anti-muscarinic effects. The morbidity and mortality from such states is high.

In patients with restricted ability to communicate coherently do remember that pain, constipation and urinary retention aggravate delirium.

Alzheimer dementia is partly a functional deficiency of acetylcholine.

Acetylcholine pathways also seem to have a dominant role both in regulating the sleep-wake cycle and in the disturbances of consciousness, attention and memory that are so central to both Alzheimer's and to delirium. Large acute changes in acetylcholine levels (eg from atropine-like drugs) seem to produce the picture of delirium, whereas slower and (?) smaller ones the picture of dementia. There is quite an overlap; but at the end of the day susceptibility to delirium is probably an index of prodromal dementia. There is an analogy with neuroleptic drugs (dopamine blockers); the lower the natural dopamine reserves, (ie, the closer one is to having idiopathic Parkinson disease) the more easily those symptoms will be precipitated by dopamine blockers.

Drugs with ‘atropine-like’ effects, ie that block muscarinic receptors, will make both dementia and delirium worse.

Acetyl cholinesterase inhibitors (AchIs) will tend to reverse that and thus improve various symptoms in both conditions. Rapid improvements in delirium can be clinically spectacular and of considerable practical value in managing what are often difficult situations. Years ago the only option was physostigmine which could only be given IV and had a very short half-life. Tacrine has for some time been the only IMI preparation available. However low utilisation has led to its recent withdrawal from the market; so the newer oral AchIs are the only choice at present.

Many patients suffering from Parkinson's develop a degree of dementia and may be very sensitive to anti-muscarinic drugs. Also, as the disease progresses 'over-driving' DA neurons with dopaminergic drug combinations gives rise to an increased frequency of toxic effects. These are manifest in both motor and mental function. Specialists in general medicine and neurology may benefit by considering problems related to mental (dys) functioning and balancing these against motor functioning. I am seeing more patients who suffer from agitation, paranoia and confusion related to toxicity of dopaminergic drugs.

Delirium: Extent of problem and morbidity

Some recent papers put more flesh on the bones of previous rhetoric.

Of 818 cases at a general surgery unit delirium developed in 11%. The length of stay in hospital was doubled for delirium (15 vs 8 days). Predicting factors for delirium:-- respiratory diseases, infections, fever, anemia, hypotension, hypocalcemia, hyponatremia, azotemia, elevated liver enzymes, hyperamylasemia, hyperbilirubinemia and metabolic acidosis.

In a study of postoperative delirium in 500 patients undergoing elective surgery 11.4% developed delirium. It was an costly disorder both for the patient, in terms of morbidity and mortality, and to the medical facility. It was the strongest independent determinant of length of stay in the hospital.

Another paper surveyed 126 patients > 65 years admitted for hip fracture. Delirium was common, persistent, and independently associated with poor functional recovery 1 month after hip fracture even after adjusting for pre-fracture frailty. For patients admitted for hip fracture delirium was present in 41%, persisting in 39% at hospital discharge (32% at 1 month and 6% at 6 months).

Use of psychotropics (probably due to anti-muscarinic effects), and benzodiazepines are independently associated with delirium.

Common precipitants of delirium postoperatively include infection, hypoxia, myocardial ischemia, metabolic derangements, and anti-muscarinic drugs.

Behavioural manifestations include: - anxiety, restlessness (often with picking at imaginary bits on bedclothes), aggression, gross sleep disturbance, wandering, delirium, acute psychosis.

Delirium is a neglected area of therapeutic endeavor and another example of the disappointing lack of enterprise in organic / liaison psychiatry. There is a repetitive preponderance of descriptive work, but generally little attention to biological investigation (eg Qnb binding assays) or drug treatment, especially acetyl cholinesterase inhibitors (AchIs). This, despite the clear logic derived from theory and experiment indicating it is reasonable to try AchIs, as well as various reports of success treating humans with acetyl cholinesterase inhibitors (AchIs), over the years. The story now extends over at least 20 years since the first reference I can (instantly) locate in my database (Stern, T. A. (1983) Continuous infusion of physostigmine in anticholinergic delirium), which I am sure is not the first.

Recent instances to illustrate the justification for this seemingly harsh comment; the authors of two recent papers in eminent general medical journals (see refs) on "management" of delirium did not even mention the possibility of using acetyl cholinesterase inhibitors (AchIs) like tacrine or donepezil to treat delirium.

This is rather surprising, and also a shame. It is a reminder of the enduring astuteness of what George Bernard Shaw wrote nearly a hundred years ago:-

"He who can, does. He who cannot, teaches"
(Man and Superman, 1903. 'Maxims: Education').

I published my two-pennyworth in 1997 (see refs below) and there have been various further similar reports since.

My advice to clinicians involved in this area is to try AchIs (become a 'doer'): the clinical benefit is so frequently so obvious so quickly that nurses (especially night-nurses) and also relatives will be grateful to an extent that may embarrass you. A little practical experience is worth an age of theorising.

If you speak with those toxicology experts who have tried acetyl cholinesterase inhibitors (AchIs) for delirium you will find their experience accords with mine.

This is one of the few instances where further research is needed: not to answer the question 'whether it works', but rather 'how well it works'.

Drugs that may precipitate or worsen delirium

Standard texts and sources indicate those drugs obviously anti-muscarinic by virtue of their mode of action. 'Revise' your acquaintance with these if need be; eg most anti-spasmodics, anti-parkinsons, anti-ememtics, all atropine / hyoscine drugs and most of their derivatives, eg loperamide, ipratropium and anti-histamines.

You will often encounter the term anti-cholinergic; however we should try to stick to 'anti-muscarinic' because it is these effects of acetylcholine that are being referred to. I have tried to use the word 'anti-muscarinic' consistently although you may note that quoted references often say 'anti-cholinergic'.

Non-psychotropic drugs known to be significantly anti-muscarinic include, in (approximate) descending order of potency:

Cimetidine, loperamide, Prednisolone, Theophyline, Lanoxin, Digoxin, frusemide (furosemide), dyazide, nifedipine, ranatidine, Isosorbide, Warfarin, Dipyridamole, Codeine.

The following drugs are reported to have some anti-muscarinic activity in assays

Alprazolam, Amantidine, Ampicillin, Captopril, Cefmandole, Cefoxitin, Chlorazepate, Chlordiazepoxide, Chlorthalidone, Clindamycin, Corticosterone, Cycloserine, Cyclosporin, Dexamethasone, Diazepam, Diltiazem, Diphenhydramine, Dipyrimadole, Flunitrazepam, Flurazepam, Furosemide, Gentamycin, Hydralazine, Hydrocortisone, Hydroxyzine, Imuran, Keflin, Oxazepam, Oxycodone, Pancuronium, Phenelzine, Phenobarbital, Piperacillin, Prednisolone, Ticrocillin, Tobramycin, Valproic acid, Vancomycin

Which psychotropic drugs have anti-muscarinic effects?

Neuroleptics
Most potent (even small doses may precipitate delirium)
Clozapine, thioridazine, chlorpromazine, olanzapine

at least 10 times less anti-muscarinic effect
thiothixene, risperidone, haloperidol, quetiapine, sertindole, ziprasidone, zotepine

This means that the first group may best be avoided in patients with, or prone to, delirium. The latter group are the drugs of choice if you feel you must use a neuroleptic.

Antidepressant drugs

  1. SSRIs, paroxetine has significant anti-muscarinic side effects, all the others are almost certainly devoid of significant in vivo effects.
  2. TCAs, all have significant anti-muscarinic side effects, desipramine the least (about equal to paroxetine)

This means that all the TCAs and paroxetine may exacerbate dementia /delirium.

Easily precipitated delirium indicates prodromal dementia. Also major surgery precipitates cognitive decline. A huge study of 1218 patients aged 60+ yrs were tested before and 1 week and 3 months after 'major' (non-cardiac) surgery. Postoperative cognitive dysfunction was present in 25.8% of patients 1 week after surgery and in 10% 3 months after surgery (compared with 3% of controls, p=0.0001). Age, duration of anaesthesia, a second operation, postoperative infections, and respiratory complications were risk factors for early postoperative cognitive dysfunction. Only age was a risk factor for late postoperative cognitive dysfunction. Hypoxaemia and hypotension were not significant risk factors at any time. These findings have implications for clinical practice and the information given to patients before surgery.

References

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