Our prospective, randomized, double-blind, placebo-controlled study was approved by the National Medical Ethics Committee at the Ministry of Health, Republic of Slovenia (protocol number 0120-8/2017-3, KME 21/01/17. The trial was retrospectively registered at ISRCTN with the submission number ISRCTN44377602. Our study adheres to CONSORT guidelines.
We studied 84 patients older than 60 years, scheduled for orthopedic hip or knee replacement surgery under SA. Written informed consent was obtained from each patient. Participant exclusion criteria were any contraindications to SA (absolute: patients’ refusal, infection at the site of injection, uncorrected hypovolemia, allergy, increased intracranial pressure or relative: coagulopathy, sepsis, fixed CO states, indeterminate neurological disease) or administration of vasoconstrictors (allergy or hypersensitivity to vasoconstrictors, unstable angina, recent coronary artery bypass surgery, recent myocardial infarction refractory arrhythmias, untreated or uncontrolled severe hypertension, untreated or uncontrolled heart failure, uncontrolled hypothyroidism, sulfite sensitivity, uncontrolled diabetes, pheochromocytoma, use of cocaine, monoamine oxidase inhibitors, phenothiazine compounds or tricyclic antidepressants).
Patients were fasted the night before the surgery. Antihypertensive medications were discontinued the day before the surgery, except the β-blockers. Midazolam 7.5 mg was given for premedication one hour before the surgery. After the patient arrival in the operating room, an IV line was inserted and the patient was placed in the lateral decubitus position. Using the paramedian approach with a 25-gauge Sprotte needle (PAJUNK, GmbH, Geisingen, Germany) we performed lumbar puncture at the L2–L3 interspace. With the needle aperture oriented in the cephalad direction, 3mL of 0.5% levobupivacaine (Chirocaine 0.5% plain; AbbVie, Campoverde, Italia) were injected within 15 seconds.
All the patients received an infusion of 1000 mL lactated Ringer solution within 45 minutes from the beginning of the measurement (500 ml before and 500 ml after SA) by opening the IV roller clamp and “eyeballing” the infusion rate. With respect to the infusion of treatment medication, the patients were randomly assigned to one of the three groups using sealed envelope randomization. The C group (control group) received an infusion of 30 ml 0.9% NaCl 30 minutes after SA. The P group (phenylephrine group) received a continuous infusion of 30 ml of 0.9% NaCl with 250 mcg of phenylephrine 30 minutes after SA. The E group (ephedrine group) received a continuous infusion 30 ml of 0.9% NaCl with 20 mg of ephedrine 30 minutes after SA. The infusion of the treatment medication in all the groups was started immediately after SA (Figure 1) via a volumetric IV pump (Alaris™ GH model 80023xx01, CareFusion).
We measured non-invasive blood pressure, non-invasive CO using thoracic electrical bioimpedance (TEB) method, heart rate and pulse oximetry (SpO2) using the AESCULON, OSYPCA MEDICAL, 2011, monitor.
We started hemodynamic measurements 5 minutes after placing the patient in the lateral decubitus position and we recorded it for 45 minutes (for 15 minutes before and 30 minutes after the injection of the local anesthetic solution into the subarachnoid space). Data on blood pressure were recorded and stored on the hard drive at 5-minute intervals and other hemodynamic data at 1-minute intervals.
The protocol for rescue treatment in the event of hemodynamic instability included:
- Severe hypotension (decrease of systolic blood pressure for more than 30% from baseline, or systolic blood pressure less than 80 mmHg): additional ephedrine boluses of 5 mg repeated in 3 minutes with additional infusion of Ringer solution or additional phenylephrine boluses of 50 mcg repeated in 3 minutes with additional infusion of Ringer solution.
- Bradycardia (≤50 beats per minute): bolus of atropine 0.5 mg, repeated in 1 minute until heart rate frequency is more than 50 beats per minute or overall amount of 2 mg atropine is reached.
- Hypertension (increase of systolic blood pressure for more than 30% from baseline): discontinuation of the ongoing infusion.
Hypotensive, hypertensive or bradycardic patients were defined as patients who developed at least one episode of hypertension, hypotension or bradycardia throughout the case and were treated according to the protocol.
Data were analyzed with the SPSS 25.0.0. software. Demographic data and baseline values were compared with one-way analysis of variance and χ2, where appropriate. The hemodynamic data before, 10, 20 and 30 minutes after SA were compared with ANOVA with Bonferroni correction for post hoc comparisons and the Student’s t-test for paired samples, where appropriate. In addition, the analysis of variance for repeated measurements with Bonferroni correction was performed to compare the change in hemodynamic measurements between the three treatment groups and the change over time. P<0.05 was considered statistically significant.
Sample size calculation to detect a 20% difference in CI (0.5 L/min/m2) between treatment groups, assuming a mean CI of 2.5 L/min/m2 and SD of 0.5 L/min/m2 with a probability level of 0.05 and a power of 0.85, yielded a sample size of 69 patients. The same number of patients would detect a 10mmHg difference between the groups in MAP (assuming SD of 10 mmHg) with a probability level of 0.05 and a power of 0.85. Expecting dropouts due to various reasons, including side effects, we randomized 90 patients. We used the G Power 22.214.171.124. software for these calculations.