Effect of creatine phosphate sodium on bispectral index and recovery quality during the general anaesthesia emergence period in elderly patients: A randomized,double-blind,placebo-controlled trial

Ethics and trial registration

The Consolidated Standards of Reporting Trials (CONSORT) recommendations were followed in this study. ¹¹ Ethical approval for this study (no. 2015-3-1) was provided by the Institutional Ethics Committee of the Jiangning Hospital Affiliated to Nanjing Medical University, Nanjing, China and this study was registered with the Chinese Clinical Trial Registry (ID: ChiCTR-IOR-16009169) on 7 September 2016. All patients involved in the study were informed of the proposal and gave their written, informed consent.

Study participants

Patients with American Society of Anesthesiologists (ASA) physical status I or II who were scheduled to undergo general anaesthesia for elective transabdominal cholecystectomy in the Department of Anaesthesiology, Jiangning Hospital Affiliated to Nanjing Medical University, Nanjing, China between March 2015 and December 2016 were eligible for inclusion in the study. Patients with drug allergies, neurological diseases, mental health diseases, a history of alcohol or narcotics abuse and those who had received alcohol, sedatives, analgesics, or opioids within the previous 24 h were excluded. To exclude patients with cognitive impairment, a mini-mental state examination was undertaken. ¹² Patients who underwent surgery with an operation time of < 30 min or > 2 h and patients with intraoperative bleeding of > 400 ml were excluded. Patients with an armpit temperature of < 36.5°C or > 37.4°C were also excluded.

Study design and randomization

This was a randomized, double-blind, placebo-controlled study conducted in two parallel groups. At the time of surgical incision, patients in group P received 1.0 g creatine phosphate sodium (Haikou Qili Pharmaceutical, Hainan, China) dissolved in 100 ml 0.9% saline administered over 30 min, while the same volume of 0.9% saline was administered to those in group C. Drugs were dissolved with 100 ml 0.9% saline in a soft plastic bottle by an anaesthesiologist not involved in anaesthesia induction. To ensure blinding, the bottles with creatine phosphate sodium or normal saline only were designated with two code letters (A and B) and the code was only broken after the statistical analysis had been fully completed. Randomization was achieved by a computer-generated table of random numbers. Both the patients and the assessors had no knowledge of the group division in the study.

Interventions and outcome measures

To decrease upper airway secretions, 0.3 mg scopolamine was injected intramuscularly 30 min before the patients’ arrival at the operating room. Patients were punctured (with 20-gauge needles) intravenously on the dorsum of the right forearm and given 0.9% saline at 300 ml/h before anaesthesia. Standard monitors (BeneView T5; Xuansheng Medical Instrument, Shanghai, China), including electrocardiography, heart rate (HR), noninvasive blood pressure measurement, pulse oximetry, and temperature, were applied. A disposable temperature monitoring probe was placed in the armpit of the patient and after 10 min the patient's temperature was monitored continuously. Alcohol-soaked cotton balls were used to clean and degrease the patients’ forehead skin. After drying, the BIS electrodes were placed in the specified positions as instructed and the BIS monitor (BIS VISTA™ Monitoring System; Medtronic, Minneapolis, MN, USA) was connected. The detection of all electrode impedance was completed.

After preoxygenation for 3 min, anaesthesia was induced with 0.3 mg/kg etomidate injected intravenously over a period of 20–30 sec. After that, 3 µg/kg fentanyl was injected intravenously over a period of 20–30 sec; then 1 min later, 0.1 mg/kg cisatracurium was injected intravenously over a period of 10–20 sec and endotracheal intubation was performed after 2 min. Tracheal intubation and mechanical ventilation were completed in 5 min. At the time of surgical incision, patients in group P were administered an intravenous infusion of 1.0 g creatine phosphate sodium dissolved in 100 ml 0.9% saline for approximately 30 min (a drop per sec) while those in group C received the same volume of 0.9% saline at the same rate. To keep the BIS value at 40–60 during the operation, anaesthesia was maintained by target controlled infusion of propofol (plasma target concentration 2.0–3.0 µg/ml) and remifentanil (plasma target concentration 2.0–3.0 ng/ml); and an injection pump of cisatracurium (0.1 mg/kg per h). Haemodynamic stability was guaranteed during the anaesthesia and recovery periods. Ephedrine (6 mg/time) was administrated when hypotension (systolic blood pressure [SBP] < 90 mmHg) occurred, and urapidil (5 mg/time) was given to treat hypertension (SBP > 140 mmHg). Atropine (0.5 mg/time) was intravenously injected when bradycardia (HR < 50 beats/min) occurred, and esmolol (10 mg/time) was used when tachycardia (HR > 100 beats/min) occurred. Cisatracurium was stopped 30 min before the operation ended, while propofol and remifentanil were stopped by the time of suturing. The doses of propofol, remifentanil and cisatracurium were recorded. An antagonist was not allowed to be used to reverse the action of cisatracurium.

Participants were observed for BIS value from T₀ to T₁₀ by an anaesthesiologist (J.L.) without knowledge of the pretreatment drug as follows: at anaesthesia induction (T₀), skin incision (T₁), cutting the gallbladder (T₂), suturing the peritoneum (T₃), skin closure (T₄), sputum suction (T₅), extubation (T₆) and 1 min (T₇), 5 min (T₈), 10 min (T₉), and 15 min (T₁₀) after extubation. The time of anaesthesia, operation duration, recovery time (from drug withdrawal to opening eyes by order), extubation time (from drug withdrawal to extubation), consciousness recovery time (from drug withdrawal to when the Steward score was > 4 points), duration that patients stayed in the postanaesthesia care unit (PACU) and the Steward recovery scores from T₃ to T₆ were also recorded. Extubation indications were as follows: (i) clear consciousness: hearing verbal instructions (e.g. open eyes); (ii) active reflection: obvious swallowing and coughing reflections; (iii) muscle strength recovery: holding strongly, looking up persistently; (iv) respiratory frequency: 16–25 times/min, tidal volume > 5 ml/kg, Sp0₂ > 95%. Steward recovery scores were as follows: (i) level of consciousness (2 points: fully awake; 1 point: response to stimulation; 0 points: no response to stimulation); (ii) degree of airway patency (2 points: coughing according to the order; 1 point: maintaining airway patency without support; 0 points: supported respiration); (iii) physical activity (2 points: conscious activity; 1 point: unconscious activity; 0 points: no limb activity). Patients could leave the anaesthesia recovery room if the Steward recovery score was > 4 points.

Statistical analyses

Based on the results of the first 20 patients in this study (10 patients per group), the BIS value at T₅ and T₆ and the Steward scores at T₇ and T₈ in group P were approximately 15% higher than those in group C. Power analysis indicated that a sample size of at least 54 per group would have a 90% power to detect a 15% increase rate with a type I error of 0.05, using a single-sided test. This study aimed to enrol 60 patients in each group.

All statistical analyses were performed using the SPSS® statistical package, version 16.0 (SPSS Inc., Chicago, IL, USA) for Windows®. Continuous variables are presented as mean ± SD and the differences between groups were analysed by mutual comparison after single factor variance analysis (one-way analysis of variance [ANOVA]). Repeated measures of variance analysis (repeated ANOVA) was used to compare values at different time-points within the same study group. Categorized variables and frequencies are presented as n of patients (%) and analysed using Mann–Whitney U-test. A P-value < 0.05 was considered statistically significant.