Hypoactive Delirium Clinical Trial
Official title:
Randomized Double-Blind Clinical Trial to Compare Haloperidol and Non-Pharmacologic Treatment Versus Non-Pharmacologic Treatment and Placebo, in Elderly Hospitalized Patients With Hypoactive Delirium
Haloperidol and Non-Pharmacologic Treatment are recognized treatments for delirium. This study will evaluate which is the best treatment for hypoactive delirium.
Background
Delirium is a cognitive disorder that affects attention and other mental functions. It has
an acute onset (in hours or days), a fluctuating course and has various conditioning factors
such as diseases or withdrawal or intoxication syndromes.
Delirium is a syndrome with multifactorial origin, it commonly presents in elderly patients,
with a prevalence of 20%. Delirium develops when basal vulnerability interacts with
precipitating factors.
Delirium has three types according to its psychomotor presentation, hyperactive (agitated),
hypoactive (tranquil) or mixed. Delirium has serious outcomes, such as prolonged
hospitalization (1), cognitive decline and dementia (2,3,4,), posttraumatic stress disorder
(5) and a higher mortality (1).
A neurotransmitter imbalance between acetylcholine and dopamine explains delirium symptoms.
A dopamine excess has various consequences: hallucinations that are present in 51 %, and
delusions, present in up to 43% in hypoactive delirium. These symptoms produce acute stress
in patients and caregivers. It is reported that 53.5% of patients recalled the episode of
delirium and from these, 55% of them recalled it associated to hallucinations and 95% of
them to delusions. Family recalled the event as stressful in 66%, nurses in 65% of those who
did not have hallucinations and in 88% of those who had (6).
Hallucinations and delusions are risk factors for the development of posttraumatic stress
disorder, which occurs in up 22% of patients.
Dopamine increase has been associated to apoptosis for its neurotoxic effects. Inflammation
has a role in delirium. A study demonstrated that cortisol, Interleukin 6 ( IL-6) and
protein S100 calcium binding protein B (S 100β) are all associated with delirium (7).
It is important to note that antipsychotics may have a neuro-protective effect by blocking
dopamine receptors, and, therefore, diminishing the potential negative outcomes associated
with dopamine excess. Furthermore in an observational study using haloperidol in the
intensive care unit there was a decrease in mortality, possibly by its effects on
inflammation, inhibiting the release of proinflammatory cytokines (8). One of the effects of
haloperidol in vitro is the induction of interleukin receptor antagonist ( IL-IRA), which
has shown to have an independent role in delirium. IL-IRA blocks the actions of Interleukin
1α (IL-1α) and interleukin 1β (IL-Iβ) . IL-IRA also downregulates ischaemic and excitotoxic
damage (9).
Treatment of Delirium
Psychiatrist, Geriatricians and Neurologists, usually, treat delirium; however treatment
strategies vary widely among disciplines, due to differences in the practice guidelines and
local applications of current knowledge among centers. An integration of their treatment
approaches could offer important clinical advantages. To refer some differences, The
American Psychiatric Association (APA) Guidelines (10) recommend treatment with
antipsychotics for elderly patients. Where haloperidol is the gold standard, with a dose of
0.25 to 0.50 mg every 4 hours, although the dose may need to be increased for those patients
severely agitated. There is no mention among all subtypes of delirium. This guideline
recognizes the non-pharmacologic intervention as part of the treatment.
On the other hand, Geriatrics Guidelines for the treatment of delirium, mention that the
treatment of delirium should be mainly based on non-pharmacologic treatment. Restricting the
pharmacologic treatment for those patients with severe manifestations of agitation (11). The
NICE Guidelines mention that pharmacologic treatment in hypoactive delirium patients is
indicated during one week to those patients with distress due to hallucinations (12).
Authors have mentioned that non-pharmacologic measures have not been assessed in clinical
trials, and that pharmacologic treatment has not been recommended at this time (13).
Furthermore, others addressed that currently, treatment with antipsychotics are used where
non-pharmacologic measures have failed to treat psychotic symptoms. Or when the safety of
patients or others are compromised, and that clinical trials with antipsychotics are few
(14).
As it was mentioned before, there is no standardized treatment of delirium among different
disciplines. Therefore, it is still on debate to determine which the best strategy in
treating delirium is.
As far as we know, there are no clinical trials adequately evaluating haloperidol as the
cornerstone of management in hypoactive delirium. Nonetheless, those patients who were
exposed to a higher dose of haloperidol improved significantly with this antipsychotic (15).
Therefore, it is not known whether hypoactive delirium (the most frequent and difficult to
recognize) should be treated with haloperidol at lower doses. Or if haloperidol should be
used only in mixed and hyperactive types of delirium. Though despite few studies that have
included patients with hypoactive delirium suggest that antipsychotics may have a role in
the treatment of this delirium subtype (16).
Statement of the Problem
Hypoactive delirium is a common condition in hospitalized elderly patients. It is the most
common type of delirium that carries more difficulty in its diagnosis. It is associated to a
longer hospital stay, increased expenses associated to its diagnosis and more doubts on the
most efficacious treatment strategy.
Surprisingly, even when hypoactive delirium is the most frequent, it is the hyperactive type
the paradigm of study, and it is the one specifically mentioned in treatment guidelines.
To the best of our knowledge, there are no studies evaluating specifically haloperidol in
hypoactive delirium. Some studies have excluded this type of delirium systematically or
include all delirium subtypes where hypoactive delirium is poorly represented/analyzed.
Significance of the Investigation
There are few clinical studies correctly designed, exempt of methodological flaws and
evaluating the most important clinical outcomes in delirium patients in general. There are
no randomized clinical trials (RCTs) testing low-dose haloperidol against non-pharmacologic
measures in the treatment of hypoactive delirium. Just few studies have included patients
with hypoactive delirium with varying results, contributing to the lack of uniform
recommendations (16). Currently, its treatment is based on the particular experiences of
each clinical center without measuring its impact on relevant outcomes.
Furthermore, there are no studies evaluating perceived stress in patients and their
caregivers, as well as posttraumatic stress in hypoactive delirium patients. None has
evaluated cognitive decline after a hypoactive delirium treated either with antipsychotics
or non-pharmacologic measures.
The purpose of the present RCT is to bring out knowledge about different treatments in
elderly patients with hypoactive delirium.
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