Anesthesia in the News
  • Could Melatonin Prevent Post-Operative Delirium (POD) in Elderly Orthopedic Patients?

    Postoperative delirium (POD) is one of the most frequent complications following surgery in elderly patients, and is associated with increased morbidity and mortality, prolonged length of stay, cognitive and functional decline leading to loss of autonomy, and important additional healthcare costs.  According to the American Geriatric Society, POD is the most common complication of surgery for older adults, affecting up to 50% of seniors.

    It has been documented that multicomponent intervention and non-pharmacological preventive measures can reduce the incidence of postoperative delirium.  However, when these measures fail or are not available, as Sigaut and colleagues wrote, “the idea that a medication could reduce the incidence of postoperative delirium incidence is interesting and potentially timesaving.”  Nevertheless, the effectiveness of pharmacological approaches for postoperative delirium incidence prevention remains unclear (Siddiqi, 2016).

    Melatonin as mitigator

    Melatonin, a natural hormone produced by the pineal gland, is known to be involved in sleep-wake cycle regulation and has been studied for a variety of uses, from insomnia and jet lag to circadian rhythm disorders in shift workers and the blind and, more recently, delirium prevention.  Recent studies suggest that preoperative cerebrospinal fluid melatonin concentrations may be correlated with delirium risk following hip fracture surgery (Scholtens et al., 2016) and that melatonin secretion rapidly declines with age (Zhdanova et al., 1997).

    To date, the use of melatonin to prevent delirium in clinical studies has been promising.  A multicenter, double-blind randomized controlled trial conducted by de Jonghe and colleagues found that melatonin decreases delirium incidence in elderly patients hospitalized in medical wards by more than 50%, passing from 31% in control group to 12% in melatonin group (P=0.014).

    Burden of disease and potential promise

    Delirium is associated with increased postoperative morbidity and mortality.  With respect to long-term outcomes, studies have demonstrated that POD is associated with cognitive decline, onset of dementia, reduced functional ability,and admission to long-term care.

    A variety of risk factors for POD have been reported including age, dementia, reduced myocardial function, electrolyte disturbance, alcoholism, smoking, increased blood transfusion needs, fluctuation of intraoperative blood pressure, and benzodiazepine usage.  POD occurs frequently in certain procedures, such as orthopedic operations, major gastrointestinal and major cardiovascular surgeries, surgery under general anesthesia, prolonged surgery, trauma, and emergency surgeries.

    It is consequently associated with ~$60,000 of incremental costs over the following year in the United States (Marcantonio, 2012).  Therefore, it has considerable consequences for patients, families, and for society.  Coupled with the ageing of the US population and increasing life expectancy, the number of elderly patients undergoing surgery increases, which raises POD as a major public health problem.

    One double-blinded prospective randomized comparative study published in late June sought to evaluate the prophylactic efficiency of melatonin for postoperative delirium in elderly patients with multifactorial risk for developing delirium undergoing orthopedic trauma surgery under general anesthesia.

    Participants and measures

    The study, conducted between July and December of 2020, was comprised of a cohort of 80 patients with multiple aggravating factors for the development of POD including old age, trauma, receiving opioids to alleviate the perioperative pain, orthopedic surgery, and receiving general anesthesia (GA).  As the investigators wrote, “to our knowledge, no adequate trials have been performed to evaluate the prophylactic ability of melatonin to mitigate the occurrence of postoperative delirium in patients with these combined challenging characteristics.”

    The inclusion criteria were operations performed in the morning, upper limb (accompanied or not with lower limb) orthopedic trauma, receiving perioperative opioids to alleviate trauma pain, surgeries performed GA, age 65 years old or more, both genders, and patients with physical status I-III.

    Patients were randomized equally into group M (melatonin group) and group NM (non-melatonin group) via computer-generated random numbers.  Each patient was assessed for relevant history and routine laboratory investigations by an anesthesiologist on the night before surgery and screened for delirium at that time with the Abbreviated Mental Test (AMT), which The Royal College of Physicians and the British Geriatric Society have recommended for regular evaluation of the cognitive functions in older persons (Dickinson, 1992).  Patients with an AMT score of <8 were assumed to have delirium.

    The primary outcome was the detection of the difference in the incidence of POD between both groups at day 3 postoperatively.


    Melatonin and placebo

    Group M was provided a 5 mg tablet of melatonin orally at 9 the evening before surgery, another 5 mg of melatonin with 15 mL of clear water 30 minutes before surgery, at 9 PM on the day of the procedure, and for the first 3 days.  Group NM was provided a 500 mg tablet of paracetamol as a placebo, as it looks similar to melatonin tablets, at the same time as melatonin tablets in group M.

    Induction of GA was done with fentanyl (2 μg kg−1), propofol (1-2 mg kg−1), and atracurium (0.5 mg kg−1).  Intubation was achieved with an oral endotracheal tube.  Anesthesia was maintained with isoflurane (1.15%), and incremental 0.01 mg kg−1 atracurium for every 30 minutes.  A 0.5 μg kg−1 fentanyl IV was administered if heart rate and/or blood pressure increased by 20% or more from baseline in response to surgical stimulation with a maximum of 4 μg kg−1.

    Postoperative pain was managed by IV 1 g of paracetamol every 8 hours, with an IV nalbuphine, as rescue analgesia, of 0.25 mg kg-1 not exceeding 0.5 mg kg-1 every 6 hours to maintain the Pain Assessment in Advanced Dementia scale (PAINAD) <4.  PAINAD was tested at times 0, 30 minutes, 2, 4, 8, 12, 18, and 24 hours.  The “zero” time was the moment of recovery from GA.

    Statistical significance

    The incidence of delirium was significantly lower postoperatively in group M (25%) relative to NM group (52.5%) (P <ƒ .001, OR=2.3. 95% CI=-0.44, +1.23).  AMT scores at post-anesthesia care unit and day 0 showed highly significant differences.  However, AMT scores had no significant difference within the 3 postoperative days.  Heart rate was significantly lower in M group after 50 minutes from the start of surgery.  Mean blood pressure, PAINAD, and sedation scores showed insignificant differences.

    The investigators’ hypothesis was that melatonin would cause a significant drop in the incidence of POD in the chosen population, and indeed, the results supported this theory, revealing a highly significant difference between melatonin and non-melatonin in the percent of patients who experience POD.

    In summary, the authors conclude that perioperative melatonin administration could decrease the incidence of POD following orthopedic trauma surgery performed under GA in geriatric patients, and that “routine prophylactic melatonin could be considered for surgeries on patients similar to this study population.”

    Read more on the promise of prophylactic melatonin in:  “Performance of Melatonin as Prophylaxis In Geriatric Patients with Multifactorial Risk for Postoperative Delirium Development:  A Randomized Comparative Study.


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