This was a randomized, controlled, single-center, single blind trial conducted at Hospital de Sabadell. The protocol was approved by the Ethics Committee of the Centre on March 2013 (CEIC Corporació Sanitaria Parc Taulí, Sabadell, reference number 2013/015). The study was registered at the European Union Clinical Trials Registry (EudraCT 2013–000846 -20) on April 9th, 2013 and at ClinicalTrials.gov (NCT01960543) on September 23rd, 2013. All patients received comprehensive information by the investigator on the study objectives, procedures and risks and signed the informed consent form before inclusion. Informed consent in front of a witness was allowed for patients unable to write or read due to physical impairment but with preserved cognitive function.
Patients aged 70 years and older requiring surgery for hip fracture repair that were suitable to receive spinal block,were included. Prior to inclusion, patients underwent cognitive examination by means of the Short Portable Mental Status Questionnaire (SPMSQ) [8, 9] and those with low scores (≥ 8 failures if elementary school, ≥ 7 failures if higher education), were excluded. Patients were excluded if they had any contraindication to B or LB (hypersensitivity to amide local anesthetics, severe aortic stenosis, heart failure or coagulopathies) or if they refused the regional anesthetic technique.
A random list was generated by the clinical pharmacology unit using Winpepi V2.67 . Sequentially numbered sealed opaque envelopes were produced containing the treatment identity for each patient. The list and a copy of the codes were kept in a file not accessible to the study team. Inclusion was confirmed by the anesthetist, who opened the first available sequentially numbered sealed code to randomize the patient. The study was blind for patients and for the anesthesiologists who evaluated the postoperative SPMSQ questionnaire.
Patients were not pre-medicated. Antihypertensive drugs were discontinued on the day of surgery and restarted at 48 h after surgery. Patients were randomly allocated (ratio 1:1) to receive treatment with racemic bupivacaine (Bupivacaine Braun 0.5%®, B. Braun Medical, S. A, Spain) or levobupivacaine (Chirocane®, Abbvie Spain S.L.U, Spain), both combined with fentanyl 15 μg, by intrathecal route. Both B and LB were isobaric. Spinal anesthesia was administered through a 25 gauge spinal needle using the midline or paramedial approach. The B and LB dose administered was 7 mg if height was < 160 cm and 9 mg if height was ≥160 cm, or when the surgical procedure was a hip prosthesis. Low doses were used with the objective to maintain the hemodynamic stability and minimize intra-operative hypotension. Supplemental oxygen administration was started after spinal injection. As per the protocol, if the anesthesia was not sufficient to initiate surgery, midazolam 1 mg and propofol 30 mg could be administered, and if not effective, general anesthesia was induced and the patient was withdrawn from the study. In the operating room patients received 300 ml of Lactated Ringer’s over 20 min. Electrocardiography, cuff for non-invasive blood pressure measurement, and pulse oximetry (Philips Intellivue MP70 Anesthesia) were used for routine monitoring. Hypotension (systolic blood pressure (SBP) < 100 mmHg) was treated with iv phenylephrine 50–75 μg, and ephedrine 5 mg in case the hypotension did not revert after two doses of phenylephrine. Bradycardia (heart rate (HR) < 50 beats/min) was treated with atropine 0.5–1 mg.
Outcomes and measurements
Patient characteristics such as ASA physical status, patient’s pathologies and treatments, type of fracture and surgery, SPMSQ and preoperative hemoglobin were recorded. In the operating room, and after spinal anesthesia, the level of sensory block (SB) was evaluated by pinprick, and motor block (MB) by the modified Bromage scale 15 min after the spinal injection, before and at the end of the surgery. The modified Bromage scale is used to measure the intensity of motor block based on the ability of the patients to move their lower extremities (0 = no paralysis, 1 = able to move knees, unable to raise extended legs, 2 = able to flex ankles unable to flex knees, 3 = unable to flex ankles, knees or hips). After surgery, SB was evaluated every 30 min until regression to L5 level.
Regional cerebral oximetry was measured by near–infrared spectroscopy using INVOS 5100 C, 7.00.0014 version (Somanetics Inc., Troy, MI, 48084 - USA). A first measure of rSCO2 was performed at entry in the operating room. A second measurement taken 2 min later was considered as the reference baseline value for each hemisphere, and values were recorded throughout the study. Regional cerebral desaturation was defined as a 20% or larger reduction in rCSO2 with respect to the ipsilateral baseline value. Routine monitoring of SBP, mean arterial pressure (MAP), HR and O2 saturation (O2 Sat) monitoring, volume of crystalloid infused, intraoperative use of vasoconstrictor drugs, postoperative hemoglobin and the need for blood transfusions, were also recorded.
The primary outcome measure was the mean proportion of intra-operative time with regional cerebral oxygen desaturation, defined as an rSCO2 relative reduction of 20% from baseline value. The area under the curve (AUC) for the intraoperative time below the desaturation threshold was also calculated (AUC rCSO2 reduced by ≥20% from baseline). Similar calculations were done using an absolute value of 50% as a cutoff point (AUC rCSO2 < 50%). Minimum values (trough rCSO2) and time to first saturation drop under the different cut off points were also recorded.
Postoperative cognitive impairment was evaluated after 5 to 7 days, by changes in the SPMSQ scores from baseline. Any adverse events related to nervous system disorders, reported by the responsible physician within 30 days after surgery were also recorded.
A sample size of 28 patients per group was calculated assuming an expected clinically relevant difference between treatments of 0.15 or higher on the mean proportion of intraoperative time with desaturation, with a standard deviation (SD) of 0.2, an alpha of 0.05 and 80% power.
Qualitative variables were described by the number of valid values and the frequency and percentage of each category, and compared between groups using Fisher exact tests. Quantitative variables were described by measures of central tendency and dispersion, and compared between groups using a Student T test or Mann-Whitney’s test, as appropriate. A post-hoc bivariate analysis using the above mentioned statistical tests was performed to explore the relationship of selected variables with intraoperative desaturation, postoperative cognitive impairment and neurological complications. Variables showing statistical significance in the bivariate analysis were included in logistic regression multivariate analyses to explore predictors of regional cerebral desaturation, cognitive impairment or neurological complications.