Treatment of Hypoactive Delirium and Outcome Measures

Hypoactive Delirium Clinical Trial

— THDOM  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02345902
• Other study ID #: InstitutoNCMNSZ
• Status: Recruiting
• Phase: Phase 3
• First received: November 7, 2014
• Last updated: April 20, 2017
• Start date: January 2016
• Est. completion date: December 2018

Study information

• Verified date: January 2016
• Source: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
• Contact: Maria Carmen Flores, MD, MSc
• Phone: 54870900
• Email: mcflormir[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Haloperidol and Non-Pharmacologic Treatment are recognized treatments for delirium. This study will evaluate which is the best treatment for hypoactive delirium.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: December 2018
• Est. primary completion date: March 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 70 Years and older

Eligibility

Inclusion Criteria:

• Patients who fulfill criteria for delirium according to CAM and DOSS

• Patients in hospitalization who are not receiving treatment for delirium

• Patients without treatment with antipsychotics for any other reason

• Patients whose legally proxy accepts to participate

Exclusion Criteria:

• Patients who have received pharmacologic treatment for delirium

• Patients with a corrected QT interval prolongation

• Patients who receive antipsychotics for any other reason

• Patients in another age group

• Patients whose legally proxy does not accept to participate

• Patients with dementia

• Patients with Parkinson disease

• Patients with arrythmias

• Patients with language or hearing disorders that impede communication

• Patients hospitalized in the Intensive Care Unit

• Patients who are receiving benzodiazepines and anticholinergics

• Patients with dopamine agonists or antagonists

• Patients who develop a severe neurologic disease

Related Conditions & MeSH terms

• Delirium
• Hypoactive Delirium
• Hypokinesia

Intervention

Drug:
• Haloperidol
haloperidol 1.25 mg P.O q.d

Other:
• Placebo
placebo 1.25 mg P.O q.d
• non-pharmacologic measures
A. Reorientation (i.e., calendar, clocks, familiar objects) B. Glasses and hearing devices for the particular patients needing such aids C. Avoidance of physical restraints D. Limitation of excessive personnel shifts or hospital room E. A tranquil and comfortable environment, especially at night, to avoid interruptions (i.e., dim light, low levels of noise) F. Adequate schedules for medication administration and to take vital signs or medical procedures G. Sleep hygiene (light in the room and movement during the day) H. Avoidance of dehydration I. Avoidance of medications use which are associated with delirium (e.g., psychoactive medications)

Locations

Country	Name	City	State
Mexico	Department of Neurology and Psychiatry. Instituto Nacional de Ciencias Médicas y Nutrición	Mexico City	DF

Sponsors (1)

Lead Sponsor	Collaborator
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

Country where clinical trial is conducted

Mexico, 

References & Publications (16)

Adamis D, Lunn M, Martin FC, Treloar A, Gregson N, Hamilton G, Macdonald AJ. Cytokines and IGF-I in delirious and non-delirious acutely ill older medical inpatients. Age Ageing. 2009 May;38(3):326-32; discussion 251. doi: 10.1093/ageing/afp014. Epub 2009 Mar 5. — View Citation

Boettger S, Friedlander M, Breitbart W, Passik S. Aripiprazole and haloperidol in the treatment of delirium. Aust N Z J Psychiatry. 2011 Jun;45(6):477-82. doi: 10.3109/00048674.2011.543411. — View Citation

Brajtman S, Wright D, Hogan DB, Allard P, Bruto V, Burne D, Gage L, Gagnon PR, Sadowski CA, Helsdingen S, Wilson K. Developing guidelines on the assessment and treatment of delirium in older adults at the end of life. Can Geriatr J. 2011 Jun;14(2):40-50. Epub 2011 Jul 7. — View Citation

Breitbart W, Gibson C, Tremblay A. The delirium experience: delirium recall and delirium-related distress in hospitalized patients with cancer, their spouses/caregivers, and their nurses. Psychosomatics. 2002 May-Jun;43(3):183-94. — View Citation

Davis DH, Muniz Terrera G, Keage H, Rahkonen T, Oinas M, Matthews FE, Cunningham C, Polvikoski T, Sulkava R, MacLullich AM, Brayne C. Delirium is a strong risk factor for dementia in the oldest-old: a population-based cohort study. Brain. 2012 Sep;135(Pt 9):2809-16. doi: 10.1093/brain/aws190. Epub 2012 Aug 9. — View Citation

Friedman JI, Soleimani L, McGonigle DP, Egol C, Silverstein JH. Pharmacological treatments of non-substance-withdrawal delirium: a systematic review of prospective trials. Am J Psychiatry. 2014 Feb;171(2):151-9. doi: 10.1176/appi.ajp.2013.13040458. Review. — View Citation

Griffiths RD, Jones C. Delirium, cognitive dysfunction and posttraumatic stress disorder. Curr Opin Anaesthesiol. 2007 Apr;20(2):124-9. Review. — View Citation

Inouye SK, Westendorp RG, Saczynski JS, Kimchi EY, Cleinman AA. Delirium in elderly people--authors'reply. Lancet. 2014 Jun 14;383(9934):2045. doi: 10.1016/S0140-6736(14)60994-6. — View Citation

Khan BA, Zawahiri M, Campbell NL, Fox GC, Weinstein EJ, Nazir A, Farber MO, Buckley JD, Maclullich A, Boustani MA. Delirium in hospitalized patients: implications of current evidence on clinical practice and future avenues for research--a systematic evidence review. J Hosp Med. 2012 Sep;7(7):580-9. doi: 10.1002/jhm.1949. Epub 2012 Jun 8. Review. — View Citation

Maclullich AM, Anand A, Davis DH, Jackson T, Barugh AJ, Hall RJ, Ferguson KJ, Meagher DJ, Cunningham C. New horizons in the pathogenesis, assessment and management of delirium. Age Ageing. 2013 Nov;42(6):667-74. doi: 10.1093/ageing/aft148. Epub 2013 Sep 25. Review. — View Citation

McCusker J, Cole M, Dendukuri N, Belzile E, Primeau F. Delirium in older medical inpatients and subsequent cognitive and functional status: a prospective study. CMAJ. 2001 Sep 4;165(5):575-83. — View Citation

Milbrandt EB, Kersten A, Kong L, Weissfeld LA, Clermont G, Fink MP, Angus DC. Haloperidol use is associated with lower hospital mortality in mechanically ventilated patients. Crit Care Med. 2005 Jan;33(1):226-9; discussion 263-5. — View Citation

National Clinical Guideline Centre (UK). Delirium: Diagnosis, Prevention and Management [Internet]. London: Royal College of Physicians (UK); 2010 Jul. Available from http://www.ncbi.nlm.nih.gov/books/NBK65558/ — View Citation

Practice guideline for the treatment of patients with delirium. American Psychiatric Association. Am J Psychiatry. 1999 May;156(5 Suppl):1-20. — View Citation

Saczynski JS, Marcantonio ER, Quach L, Fong TG, Gross A, Inouye SK, Jones RN. Cognitive trajectories after postoperative delirium. N Engl J Med. 2012 Jul 5;367(1):30-9. doi: 10.1056/NEJMoa1112923. — View Citation

van Munster BC, Bisschop PH, Zwinderman AH, Korevaar JC, Endert E, Wiersinga WJ, van Oosten HE, Goslings JC, de Rooij SE. Cortisol, interleukins and S100B in delirium in the elderly. Brain Cogn. 2010 Oct;74(1):18-23. doi: 10.1016/j.bandc.2010.05.010. Epub 2010 Jun 26. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in delirium severity	Reduction of 50% from the basal DOSS score	Participants will be followed at an expected average of nine days
Secondary	Necessity of additional open label haloperidol doses to control delirium symptoms	In case the patient develops a hyperactive state will receive haloperidol in an open label dose, 1 mg that could be repeated every 4 hours in case the agitation persists, for a maximum daily dose of 6 mg. In this way, the dose will never exceed the recommended 10 mg dose per day.; If the patient persists with a hypoactive state (absence of improvement on the DOSS score), we will increase the dose to 2.5 mg or half a tablet (of haloperidol or placebo q.d.) or 3.75 mg,three quarters of a tablet ( of haloperidol or placebo q.d.)	Participants will be followed at an expected average of nine days
Secondary	Delirium duration	Using the DOSS basal score and the CAM	Participants will be followed at an expected average of nine days
Secondary	Perceived stress	in patients, health staff and caregivers of both groups using the delirium experience questionnaire	At 24 hours after delirium remission
Secondary	Posttraumatic stress disorder	In patients of both groups using the posttraumatic stress disorder section of the Mini International Neuropsychiatry Interview	At 6 months after delirium remission
Secondary	Cognitive impairment as assessed by Montreal Cognitive Assessment (MoCA) <24 points	Number of patients with <24 points in the Montreal Cognitive Assessment at 6 months after delirium remission, as compared with the number of patients with scoring >3.5 points in the Informant Questionnaire on Cognitive Decline in the Elderly, as an estimate of the baseline (pre-delirium) state	At 6 months after delirium remission
Secondary	Cerebral blood flow as assessed by transcranial Doppler	in patients of both groups using a cerebral ultrasound	At baseline and after 24 h of delirium remission
Secondary	Side effects associated with either intervention	We will list all adverse reactions associated with haloperidol (extra pyramidal effects, arrhythmias, hypersensitivity to the drug or corrected QT interval prolongation), the medication will be stopped in case of the appearance of an life-threatening reaction. We will consider this case when a patient needs ventilator support, use of cardiac amines, hemodialysis or the use of the Intensive Care Unit. These conditions will require opening the masking and exit the patient from the study.	Participants will be followed at an expected average of nine days