Study design and participants
The STRIDE trial was a randomized, two-group, parallel, superiority trial whose principal objective was to assess the effectiveness of lighter versus heavier sedation during spinal anesthesia in elderly patients undergoing hip fracture repair. The trial was first registered at ClinicalTrials.gov under registration number NCT00590707 on 1/2008. Johns Hopkins IRB approval was obtained for the prospective STRIDE trial on 9/27/2010 (NA_00041873). All participants provided their written informed consent.
The primary outcome of the STRIDE trial was the impact of the intervention on the incidence of delirium during postoperative Day 1 to Day 5 or to hospital discharge, whichever occurs first. These results have been previously reported [10, 11]. In short, no overall difference in the incidence of postoperative in-hospital delirium was found between the intervention groups, but a significant effect modification by level of comorbidity was observed, where lighter sedation imparts lower in-hospital delirium risk in patients with low pre-operative comorbidity [10]. In addition, when comparing lighter versus heavier sedation, there is no difference in mortality or functional outcomes of elderly hip fracture patients 1 year after surgery [11]. STRIDE was conducted at a single clinical center. A detailed description of the entire trial protocol was published previously in the supplemental material of Li et al. [12].
Briefly, patients ≥65 years old who were undergoing hip fracture repair with spinal anesthesia and propofol sedation and who did not have preoperative delirium or severe dementia were randomized to receive either heavier (OAA/S 0–2) or lighter (OAA/S 3–5) intraoperative sedation. The inclusion criteria were 1) admission to Johns Hopkins Bayview Medical Center for surgical repair of traumatic hip fracture; 2) 65 years of age or older; 3) a preoperative mini-mental status exam (MMSE) [13] score of 15 or higher; and 4) receiving spinal anesthesia. The exclusion criteria included 1) receiving general anesthesia; 2) inability to speak or understand English; 3) severe chronic obstructive pulmonary disease or congestive heart failure; 4) refusal to give informed consent; 5) non-participating attending surgeon; 6) hip fractures in both hips on same admission; 7) repair of another fracture concurrently with the hip fracture; 8) prior hip surgery on the same hip to be repaired in the current surgery; and 9) preoperative delirium.
Data collection at baseline prior to surgery
Prior to surgery, baseline MMSE, modified Clinical Dementia Rating (CDR) as previously described [14], geriatric depression scale (GDS) [15], and Charlson comorbidity index (CCI) [16] were obtained, in addition to demographic information. CDR was adjudicated by a consensus diagnosis panel [10]. CDR scores were classified as follows: 0 = normal, 0.5 = mild cognitive impairment, ≥1 = dementia. Evaluations using Confusion Assessment Method (CAM) [17], Delirium Rating Scale-R-98 (DRS-R-98) [18], and abbreviated digit span test (DST) were also collected at baseline and used to confirm absence of preoperative delirium.
Intervention
After satisfactory administration of spinal anesthesia, the patient was randomly assigned to one of two groups in blocks with equal allocation, stratified by age and MMSE at baseline. Intra-operatively, one group had the depth of sedation maintained at an OAA/S score of 0–2. This was the heavier sedation group. Patients in the other group had the depth of sedation maintained at an OAA/S score of 3–5. This was the lighter sedation group.
Data collection during surgery
The propofol was titrated individually for each participant to achieve and maintain the depth of sedation required by that participant’s assigned treatment group (lighter or heavier sedation). The depth of sedation for all participants was measured by the OAA/S, administered every 15 min intra-operatively. During the intraoperative study period, the BIS was also recorded. The BIS monitor readout was covered throughout the surgery so that the Study Anesthesiologist/Anesthetist remained masked to the BIS values while administering propofol. The BIS readings served as an independent measure of the level of adherence to the trial interventions. Mean arterial blood pressure (MAP) was measured via oscillotonometry every 5 min, and automatically recorded in the electronic medical record. After surgery, the MAP values were abstracted and entered into the database. After surgery, the BIS values were abstracted, matched in time to their corresponding MAP values, and entered into the database at 5 min intervals. During surgery propofol was administered intravenously using the Alaris PC 8100 series infusion pump which gives continuous output of total volume (ml) infused. A continuous download of total propofol volume infused was obtained for each study case. From this data, the predicted propofol Ce was calculated on a minute by minute basis using the method of Schnider et al. [19]. Ce values were then matched in time to their corresponding MAP values and entered into the database at 5-min intervals.
Mean predicted Ce level (AvgCe) during surgery for each participant was calculated based on the area under the Ce measurement series from incision to end of surgery, divided by the surgery time --- the length of time between incision and end of surgery. Average OAA/S (AvgOAA/S), BIS (AvgBIS) and MAP (AvgMAP) levels during surgery were calculated using the same approach. The Ce values matched in time to the corresponding MAP values were used in the calculation of avgCe. Similarly, the BIS and OAA/S values matched in time to the corresponding MAP values were used in the calculation of avgBIS and avgOAA/S, respectively.
Prior to the administration of spinal anesthesia, approximately 6 cc of cerebrospinal fluid (CSF) was collected and stored for later analysis of AD biomarkers [14].
Statistical analysis
Distributions of baseline characteristics before surgery and measurements during surgery were described. Mean and standard deviations (SDs) were calculated for continuous variables and frequency distributions (n and %) were reported for categorical variables. Potential level of systematic bias in using AvgOAA/S and AvgBIS as proxy measures of AvgCe during surgery were assessed using Bland-Altman (B-A) plots. Given that AvgOAA/S and AvgBIS were both significantly correlated with AvgCe with negative correlations, reversed variables (5-AvgOAA/S and 100-AvgBIS, respectively) were used in the B-A analysis. Due to the differences in range of score for these 3 variables, all three variables were also standardized to have mean = 0 and SD = 1 to produce the B-A plots. Pearson correlations were calculated overall and by CDR and CCI levels. To explore whether the associations between AvgOAA/S or AvgBIS and AvgCe were influenced by cognitive measurement or comorbidity, nonparametric locally weighted scatterplot smoothing (LOWESS) fits of AvgOAA/S and AvgBIS on AvgCe were produced, stratified by the CDR score levels (0, 0.5, and ≥ 1). Similar LOWESS fits were also derived according to the CCI levels (0, 1, 2, and > 2). For ease of interpretation, nonlinear associations suggested by the LOWESS fit were approximated by linear or segmental linear models, as appropriate, in subsequent regression analyses. To better understand the relationship between AvgOAA/S or AvgBIS and AvgCe, multivariable regression analyses incorporating baseline cognitive measurements or CSF biomarkers as potential effect modifiers were performed to assess potential differentiation of associations of AvgOAA/S and AvgBIS with AvgCe by levels of these variables. Analyses were carried out using SAS 9.4, and an estimated association or interaction with p-value < 0.05 was considered statistically significant.