Patients
This prospective, single-centre, randomized, parallel-group, double-blinded trial (Chinese Clinical Trial Registry: ChiCTR 1800015141) was approved by the Ethics Committee of Harbin Medical University. The study adhered to the CONSORT guidelines and informed written consent was obtained from all patients.
After institutional review board approval (Harbin Medical University Institutional Research Board: KY2018-003), 150 Chinese patients aged 20-70 years who had an American Society of Anesthesiologists (ASA) Physical Status of II-III and underwent open splenectomy were included in this trial between March 2018 and July 2018. Patients with an ASA Physical Status of IV or higher, an allergy to local anaesthetics, a history of abdominal surgery, a body mass index < 15 kg.m-2 or > 40 kg.m-2 or severe cardiac and/or pulmonary dysfunction were excluded. Patients with acute or chronic preoperative opioid consumption or any other analgesic treatment for chronic pain before surgery, psychiatric or neurological factors (language barrier, neuropsychiatric disorder) were excluded. Patients who required postoperative mechanical ventilation, had sustained excessive haemorrhage (>1 L of estimated blood loss) or required a massive transfusion and patients with failed nerve block (the needle could not be positioned in the anatomic structure and the drugs failed to enter the interspace) were also excluded.
Study design
The 150 patients for whom TAPB and RSB were successfully established were randomly divided into 3 groups: a control group (C), a levobupivacaine group (L) and a levobupivacaine/morphine group (LM) (n=50). Patients in group C received general anaesthesia combined with RSB and TAPB with saline, and intravenous PCA for postoperative pain. Patients in groups L and LM received general anaesthesia combined with RSB and TAPB with levobupivacaine 0.2% alone or levobupivacaine 0.2% with morphine 30 mg.kg-1. The dosage of morphine was adjusted according to paravertebral block [12].
All patients were monitored by continuous electrocardiography (ECG) and pulse oximetry (SpO2). After local infiltration of lidocaine, the radial artery cannula was inserted to monitor the invasive blood pressure (BP). After induction with 0.03 mg.kg-1 midazolam, 1 mg.kg-1 lidocaine, 0.4 mg.kg-1 sufentanil, 0.5 mg.kg-1 atracurium, and 0.2 mg.kg-1 etomidate, the tracheal intubation was performed. After intubation, the patients were randomized into the groups C, L and LM. On the basis of our clinical experience, the patients in group C received intravenous PCA with sufentanil (0.04 mg.kg-1h-1) diluted into 150 ml of saline with a PCA device at a rate of 2 ml.h-1 continuously, a 2-ml bolus injection, and PCA with a 15-min lockout interval for postoperative analgesia. Patients in groups L and LM received levobupivacaine (60 ml of levobupivacaine 0.2%) or levobupivacaine combined with morphine (60 ml of levobupivacaine 0.2% and morphine 30 mg.kg-1) for postoperative analgesia. Anaesthesia was maintained with sevoflurane (expiratory concentration 1.5%) and remifentanil. Patients in group C received remifentanil (10 mg.kg-1h-1), and patients in group L and group LM received remifentanil to maintain their BP and heart rate within the range of 20% from the baseline. If the change in BP and/or heart rate (HR) exceeded 20% of baseline, 1 mg.kg-1 remifentanil or 6 mg ephedrine was injected.
Patients were randomly allocated to group C, L or LM according to a random sequence generated using Stata version 11 software (StataCorp; TX, USA). An independent anaesthesiologist who did not participate in the peri-operative evaluation prepared the drug for each group according to the allocation results. The second anaesthesiologist only performed the nerve block and anaesthesia. Another independent anaesthesiologist who was blinded to the randomization and anaesthesia results only investigated and recorded the peri-operative data.
All patients received RSB and TAPB after intubation in a supine position.
Ultrasound-guided rectus sheath block
We performed RSB at the first and second segments of the rectus abdominis muscle. In brief, under ultrasound guidance (M-Turbo- Ultrasound system; SonoSite, Bothell, WA, USA), a 38-mm broadband linear array ultrasound probe (5–10 MHz) was positioned at the level of the first segment of the subxiphoid region in the transverse plane. The needle was inserted into the skin from the left lateral side to the midline under the middle of the ultrasound probe using an in-plane technique at an angle of approximately 30 degrees to the skin. Under direct vision, we inserted the needle as described above, and after confirmation of the rectus abdominis muscle, we pierced the posterior rectus sheath. Saline was injected to confirm the placement of the needle at the posterior rectus sheath. When the needle placement into the rectus sheath was confirmed, 15 ml of saline, levobupivacaine 0.2% or levobupivacaine 0.2% combined with morphine was injected for the 3 groups after confirmation that no blood was withdrawn, leading to the appearance of a hypoechoic space. Then, RSB of the next segment was performed using the same method and the same volume of anaesthetic solution (Fig. 1a and b).
Ultrasound-guided transversus abdominis plane block
The ultrasound probe (5-10 MHz) was placed perpendicular to the rectus abdominis muscle and positioned laterally in the left rectus abdominis muscle between the subcostal margin and the iliac crest to obtain the classic view of abdominal layers, including the external oblique muscle, the internal oblique muscle, the transversus abdominis muscle, and the peritoneum. The needle was inserted into the skin from the left rectus abdominis muscle under the middle of the ultrasound probe using an in-plane technique at an angle of approximately 30 degrees to the skin. Under direct vision, after confirmation that no blood was withdrawn, we slowly moved the ultrasound probe from the left rectus abdominis muscle laterally to the left midaxillary line while advancing the needle in transversus abdominis plane. In order to expand the blockade area, when the tip of the needle had been advanced to the beginning of the transabdominal plane, the needle was inserted along the transabdominal plane, and 30 ml of saline, levobupivacaine 0.2% or levobupivacaine 0.2% combined with morphine was injected stepwise as the needle was advanced further; the goal of this technique was to ensure that the whole transabdominal plane was filled with anaesthetics. (Fig. 1c, d and e).
Procedures and measurements
Blood was collected at completion of the TAPB and then at 10, 20, 30, 60, 90, 120 and 150 min after injection of local anaesthetics so that the concentration of levobupivacaine could be measured using high-performance liquid chromatography (HPLC). Briefly, plasma was collected by centrifugation at 3000 rpm.min-1 for 10 min and kept frozen at -20℃ for subsequent HPLC (CBM-20A HPLC, Kyoto, Japan) test. The sample flow rate was set to 1.0 ml.min-1, and the detection wavelength was 210 nm. The levobupivacaine concentration was calculated according to the concentration curve of levobupivacaine hydrochloride (Hengrui, Jiangsu, China). The calculated curve of levobupivacaine showed good linearity over a range of 0.5-2000 ng.ml-1 (correlation coefficient ≥0.99).
After RSB and TAPB, the right subclavian vein was cannulated to collect blood and infuse blood or fluids, and all patients underwent standard open splenectomy [13]. To avoid the influence of the surgical procedure on postoperative pain, all enrolled patients received RSB and TAPB by the same surgery team. All patients received a left subcostal incision in the supine position. Postoperative analgesia was induced with PCA using sufentanil (0.04 mg.kg-1h-1) in the C group.
All patients received 40 μg.kg-1 granisetron to prevent PONV [14]. After extubation, all patients were transferred to the post-anaesthesia care unit (PACU). When a patient’s SpO2 was over 95% without the use of supplemental oxygen, the patient was transferred to the ward.
Blood loss, infusion (red blood cells [RBCs] and plasma) and consumption of remifentanil were recorded. Postoperative pain at rest and upon coughing was evaluated with a visual analogue scale (VAS) at 0, 2, 4, 6, 24, 48 and 72 hours after the operation. The postoperative pain was evaluated by incision and visceral pain (0=no pain, 10=worst pain). If the VAS score of any patient was greater than 4, a 3 mg intravenous (i.v.) bolus of morphine was administered, and pain was reassessed after 10-15 min [7]. Other variables were recorded, including time to first exhaust, time to first defecation, time to first oral intake, time to first off-bed activity and incidence of PONV (scored from 0 to 10). Before discharge, all patients scored their satisfaction with postoperative analgesia (poor=0; fair=1; good=2; excellent=3).
Metoclopramide (10 mg) was intravenously injected if the patients reported a severe episode of nausea (>7) or any episode of vomiting. The primary outcome was the use of analgesics over 24 hours. The pain score, sedation score, satisfaction score postoperative recovery time and PONV were secondary outcomes. To guarantee objective results, the investigator was blinded to the randomization and anaesthesia.
Sample size
According to our preliminary pilot study and our own experience, the amount of morphine used during the first 72 hours after surgery was approximately 15.8 (6.4) mg in patients who received no other analgesics. Approximately 46 patients in each group were required to detect a 25% reduction in morphine between the control and LM groups at 80% power with a two-sided alpha of 0.05.
Statistical analysis
The normality of the data was analysed with the Shapiro-Wilk test. Normally distributed data are presented as the mean (SD). Non-normally distributed data are presented as the median [interquartile range (IQR)]. Continuous data were analysed with repeated-measures analysis of variance. Normally distributed data were analysed with Student’s t-test, and non-normally distributed data were analysed with the Mann-Whitney U test. Categorical data were analysed with the chi-squared test.