The effects of melatonin the occurence of on post-operative delirium in hip fracture patients a randomized, double-blind, placebo controlled trial

Delirium is a frequent problem in acutely admitted elderly patients and is
associated with increased morbidity and mortality, prolonged hospital stay and
with increased economic and emotional costs.
The sleep patterns of patients with delirium are often disturbed, these
patients often sleep at day time and showing a fragmented sleep during the
night. Although many other risk factors may contribute, the older hospital
patient seems to be at significantly increased risk for developing
delirium.Though patients usually recover after treating the provocative factor,
delirium has a mean duration of 4 days [2-7 days]. Passing delirium is even
after hospital discharge associated with a three-times increased mortality
risk, higher institutionalisation rate and increased health care costs.
Thus, reducing the duration and severity of delirium and subsequently treatment
intensity could benefit patients in many ways and might reduce costs.

Sleep disturbances occur also more often in elderly hospital patients and have
been correlated with melatonin9;10. Melatonin, a hormone secreted by the pineal
gland and synthesized from serotonin, plays an important role in the regulation
of the sleep-wake cycle.11
The circadian rhythm of serum melatonin secretion is influenced by light and is
closely synchronized with the habitual hours of sleep. Alterations in
synchronization due to unusual working hours or airline flights are correlated
with sleep disturbances.
In ICU patients, sleep deprivation and a loss of circadian rhythm have also
been associated with melatonin. Additionally, in post-operative ICU patients
with delirium an irregular circadian pattern of melatonin secretion has been
found. Shigeta et al. showed in elderly patients with a post-operative delirium
different patterns of melatonin secretion suggesting that sleep deprivation
trigged delirium.These results all suggest a role between delirium and
melatonin.

Recently investigations into the relationship between melatonin therapy and
delirium have been undertaken. In 2004 Lewis hypothesized that exogenous
administration of melatonin might reduce delirium, as was later on successfully
demonstrated in one case report. Melatonin administration also seems to enhance
sleep time and night activity in patients with Alzheimer*s dementia where it
was administered in a randomized clinical trial showing no adverse effects.
Although Alzheimers* disease and delirium have sleep disorders and disturbances
in circadian rhythms in common, clinical evidence to confirm the potential
benefits of melatonin therapy in treating delirium is currently insufficient.
More clinical trials with melatonin therapy may supply with the evidence of
potential beneficial effects of suppletion on the course of delirium.

Although there is a high need for preventative measures because of high
prevalence, till so far, no drugs have been found preventing postoperative
delirium (POD). Haloperidol as a prophylactic drug is not effective in reducing
the incidence of POD; it can not prevent delirium in patients admitted for
surgical repair after hip fracture.
Additionally, the use of haloperidol in treating delirium is not without risks,
as in older patients the presence of delirium often indicates frailty and the
presence of many comorbidities. Haloperidol is nevertheless advised as first
choice drug in the Dutch CBO guideline Delirium (2005), although the safety of
haloperidol on the occurrence of complications, such as a prolonged QT-interval
or extra pyramidal symptoms in patients is of concern, especially in older
patients with acute illness and a higher frequency of other prescribed
medications with a prolongation on the QT-interval.

To assess whether profylactic treatment with 3 mg melatonin daily for 5 days in
acutely admitted eldery with hip fractures reduces the incidence of the
development of delirium.

Multi-centered, prospective randomized, placebo-controlled trial

Patients will receive melatonin 3 milligrams ante noctum for five consecutive
days.

Burden:
Daily Confusion Assesment Method will take ca. 10 minutes for a minimum of 8
days.
in delirious patients also a DRS and DSI will be taken, this can be done during
a normal conversation, within the same 10 minutes
In all patients a bloodsample will be taken on day 3 to asses their DNA profile.
One month and a year after admission, patients will be visited at home to asses
their cognitive and functional status by KATZ and MMSE questionnaire; these
visits will take approx. 15 minutes.
One year afetr admission the primary caregiver will be asked to fill in the
KATZ questionnaire by phone, this will take ca. 5 minutes.
Furthermore, in a subgroup of patients, who have given informed consent
separetaly, bloodsamples will be drawn on the first day post-operative and (in
case of passed delirium) on the first day of resolution of delirious symptoms.
on these days, blood will be drawn on four different times (9.00, 20.00, 22.00
and 2.00).

Some patients may directly benefit from the use of melatonin as profylaxis for
developing delirium. Others however will not receive any therapeutic benefit
from this study. However, the results may benefit the whole group of eldery
patients who are acutely admitted to a hospital. Furthermore patients included
in this trial will be closely monitored for the development of delirium and for
cognitive impairment.