Patients in the ICU with postoperative delirium have lower melatonin levels in the hour following surgery than those who do not experience this complication, findings from a small Japanese study suggest. The results also found a negative correlation between melatonin levels and sevoflurane exposure and a positive correlation between fentanyl concentrations and melatonin levels.
Alan Chaput, MD, an expert in postoperative delirium who was not involved in the research, applauded the investigators for tackling the causes of what is an often severe postoperative complication in the ICU population.
“This is a complication associated with increased morbidity and mortality,” said Dr. Chaput, associate professor at the University of Ottawa Faculty of Medicine, Ottawa, Canada.
“However,” he said, “while these results show what appears to be an association between postoperative delirium and melatonin levels one hour postoperatively, based on these findings the relationship can by no means said to be causal.”
Several previous studies in non-ICU patients who develop postoperative delirium have also found alterations in melatonin levels (e.g., Anesthesiology 2009;111:44-49). To examine this correlation in ICU patients, Moritoki Egi, MD, a researcher at the Okayama University Hospital in Okayama, and several colleagues analyzed prospectively collected data from 10 ICU surgical patients who met the Confusion Assessment Method for the ICU (CAM-ICU) delirium criteria and 23 similar patients without delirium. Both groups had a minimum of two days of ICU stay and had their plasma melatonin levels measured in the early morning on the day of surgery as well as one hour postoperatively and in the early morning on postoperative days (POD) 1 and 2.
Dr. Egi reported that delirious patients had average plasma melatonin levels of 0.45 pg/mL compared with 2.8 pg/mL in the non-delirious group, at one-hour postoperatively (P=0.037). There were no significant differences in melatonin levels preoperatively or at POD 1 and 2.
Multivariate statistical analyses controlling for several demographic and clinical variables showed exposure to sevoflurane or fentanyl significantly correlated with melatonin levels, with each 1% increase in cumulative sevoflurane exposure associated with a 0.41 pg/mL decrease in melatonin levels (P<0.01). Conversely, each 1% increase in total fentanyl dose was associated with a 0.008 pg/mL increase in melatonin levels (P<0.01). Maximal end-tidal sevoflurane concentrations also significantly correlated with lower melatonin levels at one-hour postoperatively.
Dr. Egi speculated that postoperative decreases in melatonin levels may increase the risk for delirium by triggering sleep disturbances, a known risk factor for delirium.
“If this is the case, it would be worth conducting a randomized trial to see how exogenous melatonin affects melatonin levels and whether this will have an impact on delirium,” he toldAnesthesiology News.
Dr. Chaput said that, “while multivariate regression analyses are appropriate for this type of study, I question why the statistical analysis here was done using melatonin as the dependent variable. In my mind, the dependent variable should have been the presence or absence of delirium, with melatonin included as a covariate along with other pre- and intraoperative variables, such as exposure to anticholinergic drugs in the perioperative period, which are known or suspected to be associated with postoperative delirium.
“As for the reported associations between increased sevoflurane exposure and lower melatonin levels and increased fentanyl doses and higher melatonin levels, the study is really too small to draw any conclusions,” he said.
Dr. Egi presented the findings at the 2012 annual meeting of the American Society of Anesthesiologists (abstract 267).
Orlando G. Florete, Jr., MD 