To the Editor: In a randomized controlled preliminary trial comparing effects of propofol, dexmedetomidine, and midazolam on postoperative cognitive dysfunction (POCD) in elderly patients undergoing hip or knee arthroplasty with combined spinal-epidural anesthesia, Li et al  showed that intraoperative sedation with propofol compared to dexmedetomidine can significantly decrease risk of POCD. Given that POCD is associated with major adverse consequences, for example, an increased mortality rate, reduced quality of life, and delayed long-term recovery, their findings have potential implications. However, we note that this finding is totally different from the results of a recent large randomized controlled study in elderly patients undergoing hip arthroplasty with the peripheral nerve block, in which patients sedated with dexmedetomidine have a lower risk of POCD than those sedated with propofol. We would like to ask the authors to comment on these different findings. When a randomized controlled trial is used to differentiate the real effect of one intervention on the primary endpoint, moreover, all of the other risk factors have to be standardized for the avoidance of potential bias. We noted that several important issues in this study were not well addressed.
First, the study subjects were elderly patients undergoing hip or knee arthroplasty, with a mean age of over 67 years. However, the authors did not provide the use of preoperative drugs in the baseline characteristics of patients. The available evidence shows that preoperative administration of benzodiazepine and opioid drugs is significantly associated with the occurrence of POCD in elderly surgical patients.
Second, in the design of this study, the intravenous infusion of dexmedetomidine and propofol, and intravenous bolus injection of midazolam were used to achieve light sedation with a bispectral index of 70 to 85. It must be emphasized that dexmedetomidine, propofol, and midazolam have significantly different features of clinical pharmacodynamics. For example, propofol has a rapid onset time and short duration and the best method to use this drug for sedation is the intravenous infusion. Due to a slow onset time, however, alone use of intravenous dexmedetomidine infusion to achieve a targeted sedation level is difficult if no bolus dose is given. Owing to a great individual variation of serum concentrations with the same dose, moreover, it is hard to maintain a stable sedation level by repeated intravenous injection of midazolam. The bispectral index was used for monitoring of sedation levels in this study, but the authors did not clearly describe whether three groups were comparable with respect to the depth of intraoperative sedation levels assessed by bispectral index monitoring at different time points. We are concerned that different intraoperative sedation levels by various drug administration methods in three groups would have contributed to their findings.
Third, intraoperative blood transfusion was not provided, though intraoperative blood transfusion of more than 3 units is an independent risk factor for POCD in elderly patients undergoing total hip replacement surgery. Furthermore, postoperative 7-day and 1-year POCD were assessed in this study, but postoperative complications were not provided. It has been shown that postoperative infections and respiratory complications are significantly associated with an increased risk of POCD after major non-cardiac surgery.
We believe that addressing the above issues would improve the transparency of this study and the interpretation of their findings.
Author's Reply: Postoperative cognitive problems are within different categories, and diagnosis and classification are not uniform among studies.[6,7] Postoperative cognitive dysfunction (POCD) is diagnosed using cognitive test scores to detect changes in developing postoperatively, compared with each individual patient's preoperative cognitive level of functioning. POCD affects a wide range of cognitive domains, such as memory, attention, orientation, and concentration, and some patients experience difficulties for months postoperatively. The definition and detection POCD should be based on well-described sensitivity and suitability in relation to surgical patients using intelligence test batteries developed for clinical neuropsychology.
Li et al  presented a prospective study of elderly patients receiving an elective total joint replacement under spinal anesthesia with either propofol, dexmedetomidine or midazolam sedation to evaluate the impact of the various anesthetic regimens on acute and long-term postoperative cognitive function. Age-matched patients not having surgery underwent neurocognitive testing as well to gauge the level of practice effect with repeated testing. The study reported that short term but not the long-term incidence of postoperative cognitive dysfunction (POCD) was influenced by the type of intraoperative sedation given, with propofol being associated with the least amount of POCD and midazolam the most. The study employed a well-recognized battery of neurocognitive tests administered by research personnel under the supervision of a neuropsychologist for the acute diagnosis of POCD. The design of the study using appropriate randomization, blinding and consistency in anesthetic plans was adequate. The methodology for diagnosis of acute POCD at the 7-day point was acceptable and in line with the recommendations from the International Study of Post-Operative Cognitive Dysfunction (ISPOCD) group, and did allow for comparison of this research with other studies.
In a recent large randomized controlled study in elderly patients undergoing hip arthroplasty with the peripheral nerve block, Mei et al  showed totally different results that dexmedetomidine could be associated with a lower incidence of postoperative delirium (POD) and propofol the higher. According to the study presented, the definition of POD and POCD was just based on a single neurocognitive test CAM and MMSE which made the study lack sensitivity and suitability, and did not allow for comparison of this research with other studies. Moreover, the study did not use an age-matched healthy control group to gauge the level of practice effect with repeated testing.
There are several issues about the study mentioned in the letter, We addressed as follows:
First, patients did not receive any sedative and opioids premedication (no benzodiazepines or hypnotics), and spinal anesthesia without opioid was the standard.
Second, propofol, dexmedetomidine or midazolam sedation was administrated during surgery and level of sedation was adjusted to achieve light sedation (Bispectral Index [BIS] score between 70 and 85). In the propofol group, sedation was achieved with continues infusion at 1.5 to 4 mg·kg–1·h–1. In dexmedetomidine group, patients received an initial dose of 0.6 to 0.8 μmg·kg−1·h−1 over 10 min, followed by a continuous infusion at 0.2 to 0.6 μmg·kg−1·h−1 until the end of surgery. In the midazolam group, patients received an initial dose of 1 to 2 mg, the depth of sedation was adjusted every 10 min, Repeated administration of 0.5 to 1.0 mg midazolam was given if the BIS score was not achieved. The depth of sedation was accessed every 10 min after sedative drugs infused and the infusion rate/dose of sedatives was adjusted to achieve target BIS score, so that patients were relaxed and drowsy but with a purposeful response to verbal stimulation.
Third, all patients received standardized postoperative care and were discharged to home, when they fulfilled well-defined discharge criteria. Postoperative mobilization was started on the day of surgery with support from nursing staff, and physiotherapy was started the following day. Patients were encouraged to ambulate freely and exercise according to the instructions given preoperatively. No patients experienced postoperative complications due to surgery or immobilization, such as pneumonia, pulmonary embolism, deep venous thrombosis or wound infection. Intraoperative blood salvage with cell saver was used in all patients and eight patients received an autologous blood transfusion. Only four patients needed allogeneic RBC transfusion during the perioperative period. The number of patients is too few to involve in the statistical analysis.
Conflicts of interest
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