This study shows that, in elderly patients undergoing hip fracture repair under spinal anesthesia with propofol sedation, the prevalence of delirium can be decreased by 50% with light sedation compared with deep sedation. This effect is associated with a mean reduction of almost 1 day of delirium for those in the light sedation group. These data show that, for every 4.7 patients treated in this manner, 1 incident of delirium will be prevented. For those with minimal preoperative cognitive impairment (MMSE score, ≥20) or those without cognitive impairment (MMSE score, ≥24), 1 incident of delirium would be prevented for approximately every 3.5 patients treated, indicating efficacy of the intervention even for those in these lower-risk groups.
Interpretation and generalizability of the study results require recognition that the targeted sedation level in the deep sedation group (BIS, approximately 50), although an electroencephalographic criterion often associated with general anesthesia,39
is frequently observed during propofol sedation in elderly patients during spinal anesthesia for hip fracture repair29
and other types of surgery.31
Sedation levels that correlate with this electroencephalographic criterion31
are also observed frequently during regional anesthetics and other procedures.30,32
Therefore, the sedation criterion in the deep sedation group may be more representative of actual practice than generally appreciated. Although BIS is not always tightly linked to clinical end points,44
its utility for titrating sedative levels of propofol is well supported.45-47
However, the utility of BIS may vary, depending on the pharmacological features of the sedative drug.48
Nevertheless, sedation end points used in the current study routinely occur during regional anesthesia and can be related to criteria used by clinical sedation scales, such as the Observer's Assessment of Alertness/Sedation Scale.49
The deep sedation group used significantly greater amounts of propofol compared with the light sedation group. Despite this association, propofol dose was not predictive of postoperative delirium. This finding suggests that the intraoperative sedation state itself rather than the amount of propofol administered was what contributed to the greater prevalence of delirium in the deep sedation group. The light sedation group received significantly greater amounts of midazolam than the deep sedation group. Because midazolam administration was permitted only during placement of the spinal anesthetic and was limited to no more than 2 mg, the increased use of midazolam in the light sedation group was small and likely represents efforts by the attending anesthesiologist to avoid deeper sedation in this group that could occur with a bolus of propofol during initiation of the spinal anesthetic. Regardless, given the association of delirium with benzodiazepine administration,22
the small but greater use of midazolam in the light sedation group
would have biased the study toward increased prevalence of delirium in this group.
Although the intraoperative sedation level was a modifiable risk factor for postoperative delirium, several demographic and perioperative factors were also associated with the prevalence of postoperative delirium in this study. These factors included preoperative dementia, perioperative erythrocyte transfusion, and admission to the ICU. Preoperative dementia is a documented risk factor for postoperative delirium3,7,17-20
; thus, group assignment was stratified by MMSE score. The finding that erythrocyte transfusion and ICU admission are risk factors for delirium is not surprising given the results of other studies.3,50
Because these factors are not controllable a priori, it is reassuring that no significant differences in these perioperative variables were found between treatment groups. Although duration of surgery was greater in the deep sedation group for unknown reasons, duration of surgery was not associated with an increased risk of postoperative delirium.
We determined the prevalence of postoperative delirium beginning on the second postoperative day using CAM. CAM is a delirium diagnostic instrument based on Diagnostic and Statistical Manual of Mental Disorders
(Third Edition Revised) criteria with a sensitivity and specificity of greater than 90% in elderly inpatient and outpatient cohorts36
and leads to results similar to those from the direct application of Diagnostic and Statistical Manual of Mental Disorders
(Third Edition Revised) criteria.51
Although other methods of delirium assessment exist, CAM is reliable in the perioperative period when used by trained personnel and is not excessively burdensome for a study that requires assessments on successive days of hospitalization.52
Because CAM does not permit assessment of delirium subtypes, this information was not reported. Delirium assessment beginning on the second postoperative day was chosen to avoid any concern about lingering effects of anesthetic agents during the immediate postoperative period. Because delirium in the PACU predicts later postoperative delirium with 100% sensitivity and 85% specificity, some early episodes of postoperative delirium of short duration were almost certainly not observed in the current study.4
The mechanism whereby intraoperative sedation level affects the occurrence of postoperative delirium in elderly patients has not been elucidated. Hypotheses range from a cerebrovascular origin due to decreased perfusion associated with greater anesthetic depth in more deeply sedated patients, to toxicity of the larger doses of propofol administered to the deep sedation group, to a fundamental alteration in brain activity induced by deeper sedation. Data from the current study do not support a hemodynamic origin of postoperative delirium. Intraoperative blood pressure management was standardized to prevent blood pressure deviations that might affect postoperative cognition.18,53
In addition, no differences were observed between treatment arms in the number of minutes that blood pressure deviated from the predetermined blood pressure criteria. Furthermore, the duration of hypotension was not an independent risk factor for postoperative delirium. The possibility of a toxic neural effect seems unlikely. Although the deep sedation group received higher doses of propofol, propofol dose itself was not an independent risk factor for postoperative delirium. By elimination, this finding suggests some drug-induced alteration in brain activity as the mechanism for the increased prevalence of postoperative delirium in the deep sedation group.
The neurobiologic mechanisms underlying delirium are not definitively understood, but several potential mechanisms have been hypothesized. The thalamus is the gateway for sensory input, the abnormal processing of which may characterize the hyperarousal of the delirious state.54
Moreover, the thalamus is thought to play an important role in anesthetic-induced loss of consciousness55
; intravenous and volatile anesthetics alter thalamic function, primarily through action at inhibitory γ-aminobutyric acid-mediated synapses56-60
; and γ-aminobutyric acid-mediated tone is reduced with aging.61
Furthermore, brief exposures of thalamic neurons to propofol may have longer-lasting effects.33
The results of the current study are consistent with these more fundamental observations.
One limitation of the current study is the exclusion of patients with MMSE scores of less than 15, restricting the generalizability of the results to patients with at most moderate dementia. Furthermore, dementia assessment in this study might have been more reliable using a clinical consensus, rather than primary care physician diagnosis and the MMSE. It is already well established that preoperative dementia is a major risk factor for development of postoperative delirium,3,7,17-20
which is consistent with the findings of the current study. Excluding those with severe dementia was necessary to recruit individuals who could fully participate in the study and whose dementia severity would not have obscured postoperative delirium assessment. Excluding patients with the most severe dementia may also have prevented the high likelihood of their developing postoperative delirium from masking benefits of the intervention. This concern is supported by the observation that those in the current study with higher MMSE scores were more likely to show a benefit of being in the light sedation group. Although data from this study do not indicate whether those with severe dementia or preoperative delirium would have benefitted from the intervention, there is no reason to believe that the intervention would have been harmful to these patients.